Antigen transfer and its effect on vaccine-induced immune amplification and tolerance

Abstract

Antigen transfer refers to the process of intercellular information exchange, where antigenic components including nucleic acids, antigen proteins/peptides and peptide-major histocompatibility complexes (p-MHCs) are transmitted from donor cells to recipient cells at the thymus, secondary lymphoid organs (SLOs), intestine, allergic sites, allografts, pathological lesions and vaccine injection sites via trogocytosis, gap junctions, tunnel nanotubes (TNTs), or extracellular vesicles (EVs). In the context of vaccine inoculation, antigen transfer is manipulated by the vaccine type and administration route, which consequently influences, even alters the immunological outcome, i.e., immune amplification and tolerance. Mainly focused on dendritic cells (DCs)-based antigen receptors, this review systematically introduces the biological process, molecular basis and clinical manifestation of antigen transfer.

Full text

Theranostics 2022, Vol. 12, Issue 13
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Theranostics
2022; 12(13): 5888-5913. doi: 10.7150/thno.75904
Review
Antigen transfer and its effect on vaccine-induced
immune amplification and tolerance
Yingying Shi#, Yichao Lu#, Jian You
College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, China.
#These authors contributed equally to this work.
 Corresponding author: Jian You, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, China. Office:
086-571-88981651, Email: youjiandoc@zju.edu.cn.
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
See http://ivyspring.com/terms for full terms and conditions.
Received: 2022.06.07; Accepted: 2022.07.15; Published: 2022.08.01
Abstract
Antigen transfer refers to the process of intercellular information exchange, where antigenic components
including nucleic acids, antigen proteins/peptides and peptide-major histocompatibility complexes
(p-MHCs) are transmitted from donor cells to recipient cells at the thymus, secondary lymphoid organs
(SLOs), intestine, allergic sites, allografts, pathological lesions and vaccine injection sites via trogocytosis,
gap junctions, tunnel nanotubes (TNTs), or extracellular vesicles (EVs). In the context of vaccine
inoculation, antigen transfer is manipulated by the vaccine type and administration route, which
consequently influences, even alters the immunological outcome, i.e., immune amplification and
tolerance. Mainly focused on dendritic cells (DCs)-based antigen receptors, this review systematically
introduces the biological process, molecular basis and clinical manifestation of antigen transfer.
Key words: antigen transfer; DCs-based receptor; vaccine; immune amplification; immune tolerance
Introduction
Antigen transfer is an important approach of
cell-to-cell communication, where antigenic
information is actively transmitted from donor cell to
recipient cell in the form of nucleic acid, antigen (Ag)
protein/peptide, peptide major histocompatibility
complex (p-MHC) and vaccine particle mainly at the
thymus, peripheral lymphoid organ, intestine, allergic
site, allograft, pathological lesion and vaccine
injection site through the contact-dependent path-
ways including trogocytosis, gap junctions, and
tunnel nanotubes (TNTs), and the contact-
independent extracellular vesicles (EVs) [1]. In fact,
both professional antigen-presenting cells (APCs) and
somatic cells (i.e., non-APCs) are potential
participants in antigen transfer. Specifically, Ag can
be transferred from APCs to APCs, from non-APCs to
APCs, from APCs to non-APCs, and even from
non-APCs to non-APCs, which is of vital significance
for coordinating immune elicitation/amplification
and tolerance establishment/maintenance [2].
Encompassing dendritic cells (DCs), B cells and
macrophages, APCs are a heterogeneous family with
functionally specialized subsets that mediate innate
and adaptive immunity upon local microenviron-
mental cues. Notably, DCs are the most powerful
APCs that accommodate a dual regulatory effect in
immune activation and tolerance induction. It has
been widely recognized that DCs modulate the
activation of T cells through both canonical [3] and
non-canonical [4-7] Ag presentation pathways, in
which the MHC system is flexibly mobilized to elicit
potent immune responses against virus infection [8]
and tumorigenesis [9, 10]. On the other hand, DCs are
paramount in the orchestration of both central and
peripheral tolerance. DCs promote central tolerance
during the negative selection of autoreactive T cells in
the thymus, and induce a tolerogenic or exhausted
state of T cells by driving the polarization of
regulatory T cells (Tregs) from naïve T cells in the
periphery [11]. Such versatile immune competence of
DCs is largely attributed to their inherent
characteristics, such as: 1) multiple subsets with
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functionalized phenotypes that constitute a
wide-ranging immune surveillance [12, 13], including
conventional DC (cDCs) [14-17], Langerhans cells
(LCs) [16, 17], plasmacytoid DCs (pDCs) [18], and
monocyte-derived DCs (mo-DCs) [19]; 2) rapid
sensing and chemotaxis toward sites under the
“non-self” invasion [20]; 3) diverse endocytic receptor
repertoires and Ag process systems for multi-
dimensional activation of T cells [21, 22]; and 4)
homing toward the secondary lymphoid organs
(SLOs, including lymph nodes (LNs), spleen, Peyer’s
patches (PPs), adenoids and tonsils) during
maturation to provide a timely integration of
environmental signals. Moreover, besides direct
capture of peripheral Ag [23-26], DCs are capable of
collecting antigenic information from Ag-exposed live
cells including non-leukocytes and other types or
individuals of APCs [14, 23, 27-29], serving as Ag
acceptors to ensure an all-round supervision over the
body and promote the flexible modulation of immune
activation [1] and tolerance [30].
Indeed, the existence of intercellular antigen
transfer largely reshapes our understanding about the
mode of action of vaccines. For locally administrated
vaccines, the accessibility and availability of
peripheral Ag by SLOs-resident DCs plays a central
role in the in-situ activation of T-/B- lymphocytes and
consequently determines the immunological
outcomes [31]. However, considering the poor
mobilization ability of tissue-resident DCs and the
potential cell damage caused by the “non-self” attack,
a direct contact with the source Ag may be difficult,
risky and not necessary. As a matter of fact, APCs and
non-APCs predominate at the vaccine sites can both
be positively vaccinated and act as intermediaries that
provide antigenic information to DCs, such as
keratinocytes (KCs) [32], muscle cells [33], LCs [34,
35], migratory DCs [36], macrophages and B cells. As
a matter of fact, antigen transfer from infected,
transformed, or vaccinated live cells to DCs prevents
the risk of cell damage caused by direct virus/tumor
contact, compensates the insufficient availability of
certain types of DCs to distal Ag, and enhances
specific immune responses against natural infection,
tumorigenesis and vaccine inoculation [2, 37-39].
Therefore, rationally utilize and regulate antigen
transfer for improved vaccine efficacy might
demonstrate some clinical significance. However,
current understanding about the biological process
and molecular basis of antigen transfer is insufficient
[40], which may limit the efficiency and safety of
current vaccines. Herein, mainly focused on
DCs-based Ag receptors, this review systematically
introduces the mode, location and participant of
antigen transfer, especially in the context of vaccine
inoculation, which may provide guidance for the
design and development of vaccines.
Pathological and physiological
significance of antigen transfer
Pathological significance of antigen transfer
Antigen transfer refers to the intercellular
trafficking (active behavior) of antigenic information
from the donor to the acceptor, which effectively
promotes the availability of Ag and extends the
breadth and duration of immune response. APCs, as
represented by DCs, fail to elicit immune responses
when directly exposed to viruses that are highly
invasive and cell-destructive (e.g., herpes simplex
virus (HSV), Epstein-Barr virus (EBV), cytomegalo-
virus and some influenza viruses) [37]. Likewise,
transformed or malignant cells may reshape the
microenvironment to inactivate infiltrating immune
cells, as both the number and the LNs-migrating
ability of tumor-infiltrating DCs drastically decreased
with time [41].
Under these circumstances, Ag is transferred
from infected or transformed live cells to DCs, which
greatly reduces the risk of direct virus/tumor contact
and magnifies specific immune response to natural
infection and tumorigenesis.
Physiological significance of antigen transfer
It is reported that compared to APCs, most
somatic cells (e.g., muscle cells, keratinocytes)
abundant at the sites of vaccine administration can be
positively vaccinated and even display higher
competence in nucleic acid-transfection and protein-
uptake [2]. However, these cells are generally low in
the expression of co-stimulatory molecules, which
deprives their ability of direct T-cell activation upon
vaccination. In response to this situation, Ag is
transferred from vaccinated somatic cells to the
nearby APCs to activate specific immune response.
On the other hand, tissue-resident DCs,
important components of the lymphoid organs that
far outnumber their circulating counterparts have
poor mobilization ability, which greatly limits their
accessibility to the peripheral Ag. However, these
DCs, LN-resident CD8α+ DCs in particular, have been
shown to present Ag from other cells (e.g., circulating
DCs), leading to efficient elicitation of the cytotoxic T
lymphocyte (CTL) response [38, 39]. Therefore,
antigen transfer from other cells to tissue-resident
DCs may compensate the low availability of these
certain types of APCs to distal Ag and magnifies
specific immune response.

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Figure 1. Four modes of antigen transfer. (A) Trogocytosis. Cells in close contact can directly "bite" and internalize membrane-associated Ags and/or p-MHCs from each
other. (B) Gap junction. Adjacent cells exchange intracellular antigenic information (pDNA, mRNA, Ag protein/peptide and p-MHCs) via hexamer channels. (C) Tunnel
nanotubes (TNTs). Cell-cell connection by actin-based membrane protrusions that establish cytoplasmic continuity between distant cells and enable the exchange of cytoplasmic
Ags and cell surface-associated Ags. (D) Extracellular vesicles (EVs). Donor cells bud directly from the plasma membrane to generate microvesicles containing p-MHCs and/or
membrane-associated Ags, or secrete exosomes derived from the intracellular Ag-incorporating endosomes. These microvesicles and exosomes diffuse into the extracellular
space to be captured by acceptor cells. Ag: antigen; mRNA: messenger RNA; pDNA: plasmid DNA; p-MHC I/II: peptide-major histocompatibility complex class I/II molecules.
Mode of antigen transfer
Intercellular antigen transfer is largely mediated
by the contact-dependent pathways including
trogocytosis [27], tunnel nanotubes (TNTs) [42] and
gap junctions [43], as well as the contact-independent
extracellular vesicles [15] (Figure 1). Both
microvesicles bud directly from the plasma
membrane [1] and trogocytosis [44] are able to
transfer membrane-associated Ags and functional
p-MHCs presented on the cell surface, whereas
exosomes derived from the late endosomes [45, 46],
gap junctions [47] and TNTs [48] mainly transfer
cytoplasmic Ag in the form of nucleic acid, Ag
protein/peptide, and p-MHCs.
In fact, different modes of antigen transfer are
involved in various physiological and pathological
conditions. Trogocytosis is generally observed
between cells with active membrane mobility. DCs
trogocytose membrane fragments containing
functional p-MHCs from neighboring cells are able to
initiate immune response efficiently [49]. Meanwhile,
immunosuppressive molecules transferred to DCs via
trogocytosis may lead to impaired immunity [50, 51].
Gap junctions are hexamer channels formed within
adjacent cells that facilitate the intracellular Ag
exchange. For example, pathogenic and harmless
antigen captured by gut-resident macrophages can be
transferred to migratory DCs through gap junctions to
induce protective immunity and establish oral
tolerance, respectively [52-54]. TNTs are actin-based
membrane protrusions (up to 150 µm in length) that
enable cell-to-cell connection over a longer distance.
TNTs are the main mediators of lymphatic meshwork
that support the quick activation of LN-resident DCs
and promote the efficient induction of immune
response [55]. Likewise, TNTs formed with malignant
cells or virus-infected cells may accelerate the spread
of diseases [55, 56]. EVs, on the other hand, enable a
contact-independent Ag transfer between the donor
and the acceptor. Tumor Ag transferred to DCs via
EVs may consequently promote anti-tumor immunity
or induce T-cell tolerance, depending mainly on the
form of transferred Ag and the maturation state of
receptor DCs [57-60].

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Trogocytosis
Generally, DCs phagocytize apoptotic and
necrotic debris from the extracellular space for
canonical Ag presentation and non-canonical Ag cross
presentation [61-63]. However, recent studies have
demonstrated that DCs can also obtain antigenic
information from living cells through a
contact-dependent pathway called "trogocytosis" (also
known as "nibbling", Figure 1A) [27, 40]. Trogocytosis
is an active process whereby acceptor cells conjugate
to donor cells for extraction of surface molecules and
membrane fragments [64]. In the context of antigen
transfer, membrane Ag and p-MHCs displayed on the
surface of donor cells are transferred to DCs in close
proximity via trogocytosis, which mainly involves
close cell-to-cell contact, formation of “immunological
synapse”-like structure, cross-cellular transport of
plasma membrane-associated cargos, and separation
of cells, leading to elicited immune responses or
maintained peripheral tolerance [14, 65-67]. Notably,
the special biological characteristics of DCs facilitate
the development of trogocytosis, including high
membrane deformability and elasticity, rapid sensing
and chemotaxis in respond to inflammation, and
extensive interaction with other cells [10, 68]. On the
contrary, lines of evidence indicate that macrophages,
which readily phagocytose apoptotic cells, cannot
trogocytose membrane from viable cells, possibly due
to limited expression of surface scavenger receptors
[40, 44], too acidic endosomal/phagosomal environ-
ment, or high levels of lysosomal proteases [69].
In tumor-bearing patients, compared to
apoptotic or necrotic tumor cells, live tumor cells
expressing various tumor-associated antigens (TAAs)
and tumor-specific antigens (TSAs) are the most
abundant source of Ag with high immunogenicity.
Therefore, trogocytosis of viable tumor cells by DCs
contributes to an efficient and versatile Ag
presentation for the activation of anti-tumor immune
response [44]. Meanwhile, during virus infection (e.g.,
human immunodeficiency virus (HIV) and EBV), DCs
are able to preferentially acquire viral Ag from
infected cells including lymphocytes, macrophages
and non-hemopoietic cells, without risks of
self-infection and immune dysfunction. On the other
hand, DCs directly infected by virus may serve as Ag
donors to provide sustained Ag for epidermal
resident LCs or recruited circulating DCs [70-73].
However, attention should be paid to the fact
that immunosuppressive molecules may also spread
and spoil the immune microenvironment during
trogocytosis. For example, human leukocyte
antigen-G (HLA-G), a nonclassical HLA-class I
molecule usually over-expressed by malignant cells,
can directly inhibit the function, chemotaxis and
viability of immune cells through receptor binding
[74]. Furthermore, the systemic immune environment
can be further deteriorated when HLA-G is
transferred to DCs via trogocytosis, which limits the
activation of effector T cells, promotes the expansion
of immunosuppressive cells (such as Tregs and
myeloid-derived suppressive cells (MDSCs)), and
even induces the apoptosis of immune cells,
rendering tumor cells with greater metastatic
potential [50, 51]. Similarly, virus with high
invasiveness and viability may also accelerate the
speed and scale of transmission through antigen
transfer. For example, although DCs are largely
resistant to productive virus infection, they express
high levels of C-type lectins, the main attachment
factors of HIV at the surface of dermal and mucosal
DCs. As a result, myeloid DCs, pDCs and LCs are all
susceptible to infection with HIV, leading to impaired
antigen-presenting function. In addition, follicular
DCs (FDCs) capture large quantities of HIV as
persistent reservoirs of virion to promote viral
pathogenesis. Furthermore, HIV-pulsed DCs can
transfer virion to T cells through “trans-infection”
(across the virological synapse or DC-derived
exosomes) and/or “cis-infection” (mediated by the de
novo viral production within DCs) for facilitated viral
dissemination and escaped antiviral immunity
[75-77].
Gap junctions
Gap junctions are clusters of intercellular
hemichannels mainly composed of plasma membrane
protein Connexin and formed in closely apposed
neighboring cells [43] (Figure 1B), especially in DCs, B
cells, monocytes and activated lymphocytes that have
a high expression of Connexin 43 (Cx43) [78, 79]. In
such communication channels, ions and small
molecules can be passively diffused [80]. Moreover,
gap junctions provide a pathway mediating the direct
cell-to-cell transfer of Ag in the form of nucleic acids,
proteins (molecular weights below 1 kDa, or amino
acid residues less than 11) [81, 82], p-MHCs, and other
signaling molecules [83]. Of note, Cx43-based gap
junctions are more favorable for the intercellular
transfer of MHC I-restricted peptides with molecular
weights lower than 1 kDa, instead of the theoretically
larger MHC II-restricted peptides [62, 84].
Accumulating evidence suggests that gap
junction plays an important role in the initiation and
amplification of immune responses. It’s reported that
infection with bacteria Salmonella up-regulates the
expression of Cx43 in both human and murine
melanoma cells, which promotes the formation of
functional gap junctions between melanoma cells and
adjacent DCs to facilitate the intercellular transfer of

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antigenic peptides. Consequently, DCs present Ag on
their surface to initiate specific cytotoxic T cells
against tumor growth. Notably, such Cx43-dependent
antigen transfer induces cross presentation and CD8+
T cell activation more efficient than that of standard
Ag loading in generating anti-tumor responses [85,
86]. Macrophages, although with limited capacity of
Ag cross-presentation and CD8+ T cell activation, may
serve as transfer stations of Ag to promote immune
responses. Specifically, tumor rejection Ags are
phagocytosed by macrophages [87] and subsequently
transferred to DCs through gap junction-mediated
intercellular transmission, which promotes the
maturation of DCs and augments antitumor T cell
responses [88]. Such antigenic communication
between macrophages and DCs can also be observed
in the intestine. Mazzini et al. [47, 52] revealed that
CX3CR1+ macrophages sampled over the intestine for
suspicious “non-self” substances and delivered
captured soluble Ags to DCs through gap junction.
Subsequently, Ag-exposed DCs migrated toward the
draining lymph nodes (dLNs) to prime or tolerize T
cells, depending on the microenvironmental signals.
FDCs have also been shown to form immune cell
clusters with cognate follicular B cells by
Cx43-mediated gap junction for direct Ag delivery
[89], supporting the development and maturation of B
cells in the germinal center [79].
Tunnel nanotubes
Tunnel nanotubes (TNTs) (Figure 1C), also
known as “filopodia bridges”, “membrane tubes” and
“nanotubules” [90], are non-adherent, filamentous
actin (F-actin) -based cytoplasmic protrusions [91]
widely found in immune cells, neurons, tumor cells
[56] and epithelial cells. TNTs enable cell-to-cell
communication over long distance by plasma
membrane bridges [92] (e.g., TNTs in macrophages
can extend more than 150 μm [93]), which establishes
cytoplasm continuity [94] and facilitates intercellular
information exchange. Specifically, nucleic acids,
proteins, lipid nanoparticles, organelles (such as
vesicles, lysosomes, mitochondria and
autophagosomes) and even pathogenic particles [95]
can be transported from donor cells to acceptor cells
via TNTs [42]. To date, “cell dislodgment" and
"actin-driven" are the two widely recognized
mechanisms accounting for the formation of
intercellular TNTs [96]. However, more efforts are
needed to fully address the molecular basis and
immunological significance of TNTs.
Despite insufficient understanding of
TNTs-involved Ag transfer, lines of evidence suggest
that such long and thin membrane tubes actively
mobilize the immune regulatory networks by
connecting multiple cells and promoting the
intracellular sharing of antigenic information [97]. It
should be mentioned that the unique membrane
structures of DCs including elaborate dendrites,
sophisticated pseudopodia and delicate ruffles
support the deformation and rearrangement of
plasma membrane [98, 99], which also consists the
structural basis of TNTs. Peripheral Ag-exposed DCs
migrate to the dLNs within 48 h in a chemokine
receptor 7 (CCR7)-dependent manner [14, 23], during
which DCs undergo maturation with extensive
dendritic stretching and remarkable morphological
change, laying the foundation for immune cell
communication and T cell activation [100]. Then,
LNs-resident DCs acquire Ag from their migratory
counterparts by TNTs, which increases the
availability of Ag and consequently magnifies
immune response [1, 100]. In addition, p-MHC class II
complexes and costimulatory B7 family proteins (e.g.,
CD86 molecules) are shared within two adjacent B
cells [101] or B cells and macrophages [102] through
TNTs-mediated interconnection networks, which
improves the efficiency of Ag-dependent T cell
activation and induces a wide-ranging mobilization of
the immune system.
Nevertheless, TNTs formed within tumor cells
are reported to accelerate tumor metastasis by
propagating metabolic plasticity, angiogenic ability
and therapy resistance [56]. Besides, TNTs can be
exploited by pathogens such as HIV-1 for direct
cell-to-cell spread [55].
Extracellular Vesicles
Extracellular vesicles (EVs) (Figure 1D) are small
spherical lipid bilayer particles released into the
extracellular environment by almost all types of cells,
including APCs, somatic cells and tumor cells.
According to different mechanisms of biogenesis, EVs
are mainly categorized into microvesicles (also named
as microparticles) that bud directly from the plasma
membrane [103] and exosomes secreted as a
consequence of the fusion of multivesicular
endosomes (MVEs) with the plasma membrane [104].
EVs loaded with cargos (e.g., lipids, proteins and
nucleic acids) are diffused into the interstitial space or
the circulation to be internalized by receptor cells via
phagocytosis, endocytosis, macropinocytosis, lipid
rafts-mediated internalization, or direct plasma
membrane fusion [105, 106]. EVs remain attached to
recipient cells can also transfer donor-derived cargos.
For example, during allogenic organ transplantation,
donor DCs migrate from the graft to lymphoid tissues
and transfer MHC molecules to recipient cDCs
through EVs. These EVs are internalized or remain
attached to the recipient cDCs, instead of fusing with

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the plasma membrane of the acceptor APCs, which
consequently enhanced the activation of alloreactive T
cells. In this regard, depletion of recipient DCs after
allograft can be used to delay graft rejection [107].
EVs-mediated Ag transfer from tumor cells or
virus-infected cells to DCs is of great importance to
the initiation and maintenance of specific immune
responses [15]. DCs are able to selectively engulf
cancer cell-derived EVs incorporating antigenic
protein, epitope peptide and/or p-MHCs through
extracellular vesicles-internalizing receptors (EVIR)
[45, 46], which coordinates antitumor response with
quick mobilization and high efficiency [57]. Of note,
EVs can be easily isolated from the sera or malignant
effusions of patient, representing as rich reservoirs of
the whole panel of tumor Ag that may elicit a broad
array of T cell clones against multiple Ag epitopes.
Indeed, several EVs have been collected, modified
and used as the next-generation cell-free cancer
vaccines in personalized tumor immunotherapy [108,
109].
However, EVs with insufficient co-stimulatory
signals and/or adjuvant-like components may induce
immune tolerance when internalized by immature
DCs [110]. Moreover, immunosuppressive molecules
can also be transferred through tumor cells-derived
EVs [111-114] to impair the maturation and
immunological function of immune cells.
Location of antigen transfer
A growing number of studies have
demonstrated that Ag is transferred at various
physiological and pathological compartments that
mainly include thymus [115], SLOs [1], intestine [47],
allergic sites [116], allografts [117], lesions [34, 35] and
vaccine injection sites [2], which largely determines
the immunological consequence (i.e., immune
activation or tolerance). And more efforts are needed
to unveil other potential sites, as well as the associated
outcomes, of antigen transfer.
Thymus
Thymus is primarily responsible for the
establishment of central tolerance that avoids auto-
immune responses [118]. Specifically, autoreactive T
cells are negatively selected and eliminated in the
thymic medulla before entering the periphery, which
blocks the recognition of T cell receptors (TCRs) with
tissue-restricted self-Ags and prevents specific
cytotoxic killing against normal cells [30]. Firstly, a
subpopulation of medullary thymic epithelial cells
(mTECs) displays the vast majority of autoantigens by
generating corresponding p-MHCs, a process that
involves the transcription factor autoimmune
regulator (AIRE) [119, 120]. Then, the resultant
p-MHCs are subjected to other APCs in the medullary
microenvironment such as DCs, B cells and
macrophages, especially resident CD8α+ DCs,
possibly through trogocytosis, exosomes and uptake
of apoptotic bodies that are irrespective of the
subcellular localization or expression pattern of Ag
[121]. As a result, medullary thymocytes that express
TCRs with high affinity for autoantigen-associated
p-MHCs presented by these APCs are either deleted
through apoptosis or undergo lineage deviation that
gives rise to Tregs and other ‘unconventional’ T cell
populations [122]. Notably, during negative selection,
CD8+ and CD4+ single positive T cells may travel at a
rate of 10 μm per minute in the medullary areas to
increase the interaction with these APCs [123]. It
should be mentioned that scavenger receptor CD36 is
involved in the process of antigen transfer from
mTECs to DCs in the form of EVs that contain mTECs
cell surface proteins (i.e., intact p-MHC class I and II
complexes) [115]. However, more efforts are needed
to unveil the mechanistic details of such EVs-engaged
antigenic communication and explore the
participation of other antigen transfer approaches.
Secondary lymphoid organs
SLOs, especially LNs and spleen, are highly
organized structures that filter lymph and blood for
suspicious Ags in these fluids, allow the entry of
Ag-loaded DCs, and facilitate the antigenic interaction
between DCs, B cells and T cells, serving as the
“transit hubs” of adaptive immunity. There are a
variety of specialized stromal cells, bone marrow cells
and lymphocytes constituting the structural
organization of SLOs for efficient Ag encounter and
intercellular transfer. For example, LNs are
anatomically composed of paracortex (T cell zone),
cortex (B cell zone with follicles and germinal centers)
and medulla (including subcapsular sinus (SCS),
medullary sinuses, medullary cords and hilus) [124].
These functionalized compartments are closely
connected to orchestrate immune response against
foreign substances.
Circulating DCs migrate back to the LNs upon
peripheral Ag stimulation through afferent lymphatic
vessels and in a chemokine-dependent manner for Ag
transfer and lymphocyte activation [125, 126].
Notably, the T cell immunity elicited within SLOs is
found to be compartmentalized by route of lymphatic
transport. In response to the administration of
vaccinia virus (a replication-competent live
attenuated vaccine), skin DCs fail to relocate to the
dLNs from site of infection, which ablates vaccine
efficacy [127]. To delineate the underlying
mechanisms, O'Melia et al. [128] designed a suite of
nanoscale biomaterial tools to track and quantify the

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Ag access and presentation within LNs, thereby
optimizing antitumor CD8+ T cell responses [121].
They found that in the melanoma context, the extent
of Ag presentation by dLNs-resident APCs remained
unchanged despite the sustained access of lymph-
draining Ag while the presentation of cell-transported
Ag was increased, which was partially caused by the
phenotypes of DCs accessed via different lymphatic
transport mechanisms. Specifically, passively drained
Ag was presented mainly by pDCs and cDCs that
displayed an immunosuppressive phenotype. In
contrast, actively transported Ag was presented by
dDCs and LCs that exhibited an immunepotentiating
phenotype. However, the complex communication
among different cells, especially the intercellular
antigen transfer, is still incompletely understood.
More detailed discussion of intra-SLOs antigen
transfer can be found at the following chapters (i.e.,
5.1 From APCs to APCs).
Generally, antigen can be transferred within the
SLOs in multiple forms, including Ag
protein/peptide, Ag-encoding nucleic acid, functional
p-MHC, immune complex, and vaccine particle. More
importantly, the form of Ag may affect the mode and
even the immunological consequence of Ag transfer.
In SLOs, LNs in particular, exogenous Ag or Ag
fragments (i.e., antigenic complexes, protein and
peptide) transferred to DCs by trogocytosis, EVs,
TNTs or gap junctions can be canonically presented
on the MHC class II molecules to activate specific
CD4+ T cells [3, 62, 129] or cross-presented via the
MHC class I molecule-restricted pathway to initiate
specific CD8+ T cells [63]. Meanwhile, Ag-encoding
nucleic acids (e.g., mRNA, pDNA) transferred to DCs,
probably through EVs, TNTs or gap junctions, can be
translated into “endogenous Ag” and then
preferentially presented on the MHC class I molecules
or undergo Ag translocation to the endosomes for
MHC class II-favored cross presentation [6, 7, 130,
131]. Besides, functional p-MHC I and/or p-MHC II
can be transferred to DCs mainly through
trogocytosis and EVs, which facilitates an efficient
elicitation and magnification of T-cell responses [49,
132-134].
Intestine
Chronically exposed to both innocuous and
pathogenic Ags, intestine constitutes the largest and
most complex part of the immune system where
acquired oral tolerance to harmless dietary proteins
and commensal bacteria is established while specific
immune response against pathogenic microbes can be
elicited [135]. It is increasingly recognized that in the
intestine, antigen transfer among phagocytes with
specialized functions [136] plays a vital role in
mediating the balance between tolerance (Figure 2A)
and protective immunity (Figure 2B).
Intestinal APCs, especially DCs, are in
dispensable for triggering peripheral Foxp3+ Tregs
polarization from naïve T cells and inducing oral
tolerance [137, 138]. And default responses to
harmless Ags may otherwise lead to food allergies,
inflammatory bowel disease, and even colorectal
cancer [139, 140]. Mazzini et al. [52] found that soluble
food Ags are internalized by gut-resident CX3CR1+
macrophages and quickly transferred to migratory
CD103+ DCs in a Cx43-dependent and plasma
membrane-required manner (i.e., through gap
junction), which consequently promoted Treg
differentiation and induced oral tolerance to these
Ags. Meanwhile, McDole et al. [141] suggested that in
steady state, goblet cells in the epithelium of small
intestine transported low molecular weight soluble
Ags from the intestinal lumen to tolerogenic CD103+
DCs in the lamina propria to promote intestinal
immune homeostasis. However, the underlying
mechanisms accounting for such Ag transfer from
goblet cells to DCs remain to be fully elucidated.
Segmented filamentous bacteria (SFB) and other
intestinal resident commensal bacteria adhere tightly
to intestinal epithelial cells (IECs) via hook-like
structures, and Ag proteins from these bacteria can be
transferred into the cytosol of IECs through
adhesion-directed endocytosis to affect host T cell
homeostasis [142]. Specifically, at the tip of the
SFB-IEC synapse, SFB generates endocytic vesicles
containing microbial cell wall-associated proteins,
including an Ag that induces mucosal T helper type
17 (Th17) cell differentiation, to be acquired by host
IECs for elicitation of specific T cell responses.
On the other hand, intercellular antigen transfer
might also occur in the context of gastrointestinal
infections that consequently induces protective
immune defense against potentially pathogenic Ags
[53, 54]. In the rectal mucosal biopsies of patients with
acute campylobacter colitis or cholera, mononuclear
phagocytic cells (mainly macrophages and DCs) in the
superficial rectal mucosa exhibit a higher prevalence
of ultrastructural features of activation. Macrophages
are found to actively insert pseudopodia through
intestinal epithelial cell gaps to capture pathogenic
Ag, while DCs that are superior in Ag presentation
and T cell activation display active membrane
processes, enhanced macropinocytosis and elevated
phagosomal/lysosomal activity [143], indicating that
macrophages and DCs might share antigenic
information within the intestine through multiple
pathways to coordinate the anti-infection immune
responses.

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Figure 2. Antigen transfer in the intestine. (A) Intercellular transfer of harmless Ag establishes intestinal homeostasis. Gut-resident CX3CR1+ macrophages (Mφ)
continuously sample the gut lumen for harmless soluble Ag, including Ag from dietary proteins and commensal bacteria. Subsequently, Mφ captured Ag is transferred to intestinal
migratory CD103+ DCs, which then migrate back to the dLNs to induce T cell tolerance, establishing intestinal flora homeostasis and preventing food allergy. (B) Intercellular
transfer of pathogenic Ag induces pro-inflammatory responses against infection. Upon intestinal invasion of pathogenic bacteria and viruses, CX3CR1+ Mφ collect potentially
pathogenic Ag from infected intestinal tissue cells or directly from the pathogen, which was further transferred to CD103+ DCs through gap junctions and EVs for presentation
and T cell activation, inducing specific protective immune responses.
Allergic sites
Allergy, also termed as allergic disease or
anaphylactic reaction, refers to hypersensitivity of the
immune system in response to the exposure of
typically harmless Ags. To date, mounting evidences
have suggested that intercellular transfer of
immunoreactive substance or Ag is closely associated
with the development of exaggerated immune
response to allergens such as pollens, dust mites,
furry animal dander, drugs and foods.
Mast cells (MCs) are well recognized as key
effector cells of allergic reactions, which respond to
endogenous or exogenous danger signals by secreting
a plethora of mediators including histamine,
proteases and cytokines in the form of mast cell
granules (MCGs) that can be released by
degranulation within seconds on activation to initiate
immune responses, neutrophil recruitment and
allergen clearance. On skin inflammation,
MCs-exocytosed intact MCGs are engulfed by and
degraded within dermal DCs to promote DC
maturation and migration to the dLNs for subsequent
T cell priming [144]. In turn, it is reported that
CD301b+ perivascular DCs continuously sample the
blood and relay Ag to neighboring MCs and other
DCs through an active discharge of surface-associated
Ags on microvesicles (MVs) generated by vacuolar
protein sorting 4 (VPS4) to potentiate inflammation
and anaphylaxis against blood-borne Ags [115].
Moreover, in the case of allergic asthma and atopic
dermatitis (AD), the interplay between tissue
structural cells and DCs is largely responsible for
CD4+ T helper type 2 (Th2) cell-induced dysregulated
type 2 inflammation (Th2 sensitization) to
environmental allergens [145]. For instance, when
exposed to house dust mite (HDM), airway epithelial
cells generate danger-associated molecular patterns
(DAMPs), chemokines and cytokines to recruit,
activate and skew DCs toward Th2 phenotype that
promotes the pulmonary inflammatory reactions.
Whereas skin KCs recognize HDM through Toll-like
receptors (TLRs) and produce type 2 immune
cytokines to activate cDC2 subsets and induce their
migration to the dLNs for elicitation of Th2 response.
Moreover, individuals with autoimmune diseases,
such as systemic lupus erythematosus (SLE) that
produces systemic inflammation in multiple organs,
have platelets that continuously recruit and release
mitochondrial DNA (mtDNA) as a source of
circulating autoantigen to exacerbate the self-attack of
immune system [146].

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Allografts
Similar to that of allergy, the rapid acquisition of
antigenic information from allograft by host APCs
induces severe immune rejection and graft organ
necrosis. During allogeneic organ transplantation,
host DCs rapidly integrate intact donor p-MHC class I
complexes through cross dressing or uptake and
process donor Ags into allopeptides bound to
self-MHC molecules, which induces massive
proliferation of reactive T cells and leads to graft
rejection [147, 148]. In addition, donor DCs migrated
from the graft to the SLOs may release EVs to facilitate
an efficient passage of donor MHC molecules to host
cDCs, which triggers full activation of alloreactive T
cells and impedes graft survival [107]. On the other
hand, DCs in successfully transplanted patients
undergo continuous transfer of p-MHCs from donor
DCs and/or donor somatic cells to DCs, and these
MHC-dressed DCs may induce immune tolerance to
benefit a long-term graft survival by upregulating
their own programmed death-ligand 1 (PD-L1) [149].
In order to minimize the Ag transfer-associated
graft rejection, Borges et al. [150] incubated skin grafts
with the anti-inflammatory mycobacterial protein
DnaK, which promoted a March 1-dependent
reduction of MHC class II molecules on donor CD103+
DCs, thereby inhibiting the transfer of p-MHCs to
recipient DCs and prolonging the survival of
transplanted skin. Meanwhile, Zhang et al. [151] used
CRISPR/Cas9 to ablate costimulatory CD40 at the
genomic level in DCs dressed with donor p-MHCs to
inhibit their maturation and LNs-homing, which not
only induced long-term graft tolerance but also
prevented severe immunosuppressive side effects.
Pathological lesions
Antigen transfer at the lesions (e.g., sites under
physical damage, chemical stimulation, ultraviolet
irradiation, pathogen infection and tumorigenesis)
may serve as a critical line of immune defense. For
example, in human skin models and genital herpes
lesion biopsies, HSV is first taken up by LCs that
patrol over the epidermis. Subsequently, HSV-loaded
LCs migrate to the dermis and transfer HSV Ag to
CD103+ cDCs with a superior antigen-presenting
ability and more motivated LNs-homing for initiation
of immune response (passive Ag transfer, as
HSV-infected LCs undergo apoptosis to be further
taken up by dermal DCs) [152, 153]. Notably, cDC1s
that feature high expression of C-type lectin-like
receptor 9A (CLEC9A) are capable of binding
dead-cell debris and promoting the cross presentation
of corpse-associated Ags, which facilitates their relay
of Ag from the donor cells or directly from the
pathogens [154, 155]. Moreover, during skin
inflammation, an intensive and long-lasting
synapse-like contact between migratory DCs and
stationary MCs culminates in the functional transfer
of DC-restricted proteins to MCs, including MHC
class II complexes, which may ensure the host defense
during DC migration to the dLNs or critical periods of
migration-based DC absence [156]. In the context of
tumorigenesis, p-MHC class I complexes and other
membrane structures containing the “non-self” Ags
that presented on the surface of tumor cells can be
directly transferred to DCs via trogocytosis [44], while
intracellular Ags can be transmitted to DCs through
exosomes [157]. Squadrit et al. [57] reported a
lentivirus-encoded chimeric receptor named
extracellular vesicle-internalizing receptor (EVIR) to
facilitate the specific and efficient uptake of cancer
cell-derived EVs by DCs, which exploited the cross
dressing of pre-formed p-MHC class I complexes for
improved activation of specific T cell responses
against tumor.
However, as aforementioned, some immuno-
suppressive molecules might also be transferred to
immune cells through trogocytosis, gap junctions,
TNTs and EVs to modulate immune responses and
promote disease progression [50, 51, 74]. For example,
natural killer (NK) cells acquire carcinoembryonic
antigen (CEA) from the surface of CEA-expressing
cells via trogocytosis and exhibit inhibited cytolytic
activity and dampened degranulation function [158];
T cells exposed to tumor-derived exosomes
incorporating PD-L1 display suppressed activation in
the dLNs [159]; and TNT-connected astrocytoma cells
may promote tumor progression and resistance to
therapy [160].
Vaccine injection sites
Prophylactic and therapeutic vaccines are
generally administrated into the intramuscular,
subcutaneous or intradermal compartments. Different
physiological sites differ in the cell type, cell
abundance and lymphatic system. Therefore, the site
of vaccine inoculation may affect the efficacy of Ag
transfer as well as the strength and duration of
immune response [2].
For example, upon intramuscularly injection,
self-amplifying mRNAs (SAM®)-encoded Ag is
expressed by muscle cells and then transferred to
nearby APCs, which consequently promotes the
activation the CD8+ T-cell responses [33]. In addition,
mRNA-based vaccine is taken up by both immune
and non-immune cells in the skin upon intradermal
administration [32]. Functional Ag may be expressed
by these vaccinated non-immune cells and then
transferred to APCs to promote the induction of
adaptive immunity. Moreover, studies suggest that

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many keratinocyte-specific molecules can be
transferred to epidermal-resident LCs as mRNA and
protein probably via TNTs or dendrites [161, 162].
Administrated vaccine antigen internalized by
non-APCs at the injection site can be transferred to
tissue-resident APCs or migratory DCs. Meanwhile,
migratory DCs may migrate towards the draining
SLOs and transfer both directly captured and
indirectly acquired (transferred from non-APCs) Ag
to LN-resident or splenic DCs. Detailed information
will be discussed in the following sections.
Participant of antigen transfer
The phenomenon of antigen transfer was
initially identified in T cell activation. In fact, within
minutes of cognate T cells interacting with APCs,
p-MHCs on the surface of APCs form clusters at the
site of T cell contact. Subsequently, clusters containing
p-MHCs are internalized by T cells via TCR-mediated
trogocytosis. As a result, T cells are subjected to the
Ag-specific cytolysis by neighboring T cells (termed
“fratricide”), which may lead to suppressed T cell
immunity [163]. Meanwhile, T cells may also acquire
p-MHCs from other target cells through
contact-dependent immunological synapses, and
Tregs are especially adept at removing MHC class II
and costimulatory molecules from APCs via
trogocytosis to induce immune tolerance [164]. In
addition to T cell-based Ag receptors, NK cells [165,
166] and basophils [167] can also acquire Ag from
APCs, thereby impacting the potency, durability, and
even consequence of immune responses.
Generally, antigen transfer is a reciprocal
interaction that theoretically can occur between any
cells with active membrane mobility, including that
from APCs to APCs, from non-APCs to APCs, from
APCs to non-APCs, and even from non-APCs to
non-APCs. In this review, we focus on DCs-based Ag
receptors and the associated immunological outcomes
(Table 1).
Table 1. Antigen transfer with APCs-based receptors
Donor cell
Acceptor cell
Pathway
Ag form
Location
Immunological outcome
Ref.
APCs to APCs
Migratory cDC1
LNs-resident cDC1/2
TNTs, EVs, trogocytosis,
gap junctions
p-MHC I/II
LNs
Initiate anti-tumor immune response
[1, 48, 55,
134]
pDCs
cDC1
EVs
antigen protein/peptide, or
p-MHC I
LNs
Cross prime CD8
+
T cells and induce
durable immunity
[132, 133]
B cells and FDCs,
respectively
FDCs and B cells,
respectively
EVs
p-MHC II
Follicle
Immunocomplexes deposit on FDCs
and cognitive B cells differentiation
[183, 184]
LCs
Dermal cDCs
EVs, trogocytosis, gap
junctions, TNTs
Processed Ag and intact
p-MHCs
Skin
Induce immune defense against
HSV
[152]
B cells
mo-DCs
Possibly by EVs,
trogocytosis, gap
junctions, TNTs
Processed Ag and intact
p-MHC II
/
Mo-DCs obtain processed Ag to
activate T cells
[280]
Macrophages
DCs
Gap junctions
Dietary Ag
Intestine
Establish oral tolerance
[52, 206]
Macrophages
DCs
Gap junctions, EVs
Ingested or processed Ag
Intestine and skin
Resist the infection by
Mycobacterium, Salmonella, Listeria
and other pathogens
[176, 178,
211]
Macrophages
B cells
Possibly by gap
junctions, TNTs
p-MHCs
Lymphoid
follicles
Initiate the early activation of
cognate B cells
[183]
B cells
B220
+
Macrophages
EVs
Processed Ag fragments or
Ag particles
Peritoneum
Macrophages acquire the ability to
activate CD4
+
T cells
[187]
cDCs
B cells
Possibly by gap
junctions, TNTs
Processed Ag fragments, Ag
particles and intact p-MHC II
Lymphoid
follicles
Activate cognate B cells
[180, 185]
Non-APCs to APCs
Gene edited 4T1/
B16 tumor cells with
high expression of
MHC I/II
Tumor infiltrating
cDC1
Possibly by EVs,
trogocytosis, gap
junctions, TNTs
p-MHC I/II
Tumor site
Activate tumor specific CD4+ T cells
[189]
Fibrosarcoma tumor
cells
cDC2
Possibly by EVs,
trogocytosis, gap
junctions, TNTs
p-MHC I
Tumor site
Promote antitumor CD8
+
T cell
immunity
[190]
Melanoma cells and
epithelial cells near
the colorectal tumor
pDCs
Possibly by EVs,
trogocytosis, gap
junctions, TNTs
p-MHC I
Tumor site
Compensate the poor cross
presentation and phagocytic ability
of pDCs
[191]
Tumor cells and
commensal bacteria,
respectively
Intestinal commensal
bacteria and DCs,
respectively
Possibly by EVs, TNTs,
trogocytosis
p-MHC I
Tumor site,
intestine
Upregulate reactive IFN-γ
+
T cells
and sensitize immune checkpoint
blockade efficacy
[202-205]
UVB irradiated
mutate melanocytes
Skin-resident DCs and
tumor infiltrating DCs
Possibly by EVs,
trogocytosis, gap
junctions, TNTs
Possibly p-MHC I
Tumor site,
mutated skin
Promote the cure rate of malignant
melanoma
[281]
HCV or HCV infected
hepatocytes
pDCs
Contact-dependent gap
junctions, TNTs, EVs
HCV RNA
HCV infected
liver
Triger TLR 7 activation induced
type-I IFN release by pDCs to inhibit
HCV infection
[192, 193]
KCs
Multiple DCs subsets
in skin and LNs
Possibly by EVs,
trogocytosis, gap
junctions, TNTs
Ag-encoding mRNA and
protein
Vaccine injection
site and draining
LNs
Induce an enhanced immune
response without immune cell
depletion upon repeated inoculation
[32]

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Donor cell
Acceptor cell
Pathway
Ag form
Location
Immunological outcome
Ref.
of mRNA vaccine
Muscle cells
Mo-DCs
Possibly by trogocytosis,
gap junctions, TNTs
mRNA transfected Ag
fragments and/or p-MHC I
Vaccine injection
site
Elicit potent Ag-specific CD8
+
T cell
immune responses
[33]
KCs
LCs
TNTs
Ag-encoding mRNA and
protein
Vaccine injection
site
Promote vaccine effect
[161, 162]
Symbiotic bacteria
and IECs
IECs, macrophages,
and DCs
Gap junctions, EVs
Ag fragments
Intestine
Maintain intestinal homeostasis
[136, 142,
282]
mTECs
Thymus-resident
CD8α
+
DCs
EVs
p-MHC I/II
Thymus
Establish central tolerance
[115, 122]
Graft cells
DCs in organ recipients
Trogocytosis, EVs
p-MHC I
Transplanted
organ
Induce activation and proliferation
of allergen-reactive T cells
[107, 147,
148]
Mast cells
DCs
EVs
Possibly ingested and/or
processed Ag fragments, Ag
particles, and intact p-MHC
II
Near the allergic
site
Induce acute inflammatory injury,
such as severe vascular leakage, at
the allergic sites
[144]
Epithelial cells
DCs
Possibly by EVs,
trogocytosis, gap
junctions, TNTs
Possibly ingested and/or
processed Ag fragments, Ag
particles, and intact p-MHC
II
Allergic skin
Cause allergen-associated Th2
immune responses
[145]
Platelets
DCs, Macrophages
EVs
Mitochondria DNA and
multiple autoantigens
Kidney
Aggravate systemic lupus
erythematosus
[146]
From APCs to APCs
It is widely recognized that DCs, especially
cDCs, are indispensable coordinators of the adaptive
immunity, yet elicitation of specific immune response
may not rely solely on the direct antigenic stimulation
on DCs. Accumulating evidence suggests that Ag or
Ag complex can be transferred from other types or
individuals of APCs to DCs [168] (Figure 3),
contributing to an improved availability of Ag that
mobilizes the immune system with higher efficiency.
DCs and DCs
S.L. Nutt et al. [79] have summarized that
heterogeneous DCs subpopulations are closely
associated with each other in the systemic immune
network despite distinct developmental, locational,
phenotypical and functional hallmarks, which
constitutes the immunological basis of T cell
activation and tolerance [169, 170].
It is reported that in response to CD40L-
expressing Th cells or recombinant CD40L, networks
of TNTs are induced by DC1 (i.e., DCs matured in the
presence of inflammatory mediators of type-1
immunity) to support the direct intercellular transfer
of endosome-associated vesicles and Ag between DCs
[55]. Aline et al. [171] demonstrated that DCs-derived
exosomes encompassing functional MHC class I/II
and costimulatory molecules were capable of
inducing protective immunity against toxoplasmosis,
serving as a novel cell-free vaccine. Specifically, part
of the adoptively transferred Toxoplasma gondii-pulsed
DC-derived exosomes accumulated in the spleen and
were most likely internalized by spleen-resident
CD8α+ DCs, which elicited a strong systemic T helper
type 1 (Th1)-biased specific immune response. In
addition, protein antigens in DCs-derived exosomes
can be transferred to and presented by recipient DCs
to induce the activation of allogeneic T cells, which
may be used to facilitate cancer immunotherapy [172,
173]. On the other hand, inflammatory signals induce
the LNs-homing of migratory cDC1 and its
subsequent Ag transfer to LNs-resident DCs through
tight synaptic interaction [15], which facilitates the
accumulation of Ag in LNs-resident DCs for
activation of specific effector CD8+ T cells [1]. pDCs,
formerly known as natural interferon producing cells
(NIPCs), are the main producers of type I Interferon
(IFN) [18] and play a key role in antiviral immunity.
Although the capability of pDCs to generate in vivo
cross-primed CD8+ T cells remains controversial, they
have been shown to transfer antigen (possibly Ag
protein, peptide, or p-MHC I [133]) to the bystander
cDCs via EVs, which leads to efficient cross-priming
of naive CD8+ T cells and induction of durable
immunity. Notably, although both cDC1s and cDC2s
are capable of acquiring Ag from pDCs, cDC1s,
instead of cDC2s, are required for CTL activation
upon pDCs-targeted vaccination [132]. Furthermore,
monocytes loaded with protein or peptide antigen can
transfer Ag to splenic DCs through cell-cell contact
and the formation of Cx43-containing gap junctions,
which leads to efficient activation of CTLs and potent
antitumor responses [174].
Macrophages and DCs
With intricated membrane structures and
dynamic membrane activities, macrophages and DCs
are closely associated in the context of antigen transfer
(Figure 2). Although macrophages prevail in
phagocytosis, their ability of Ag cross presentation is
far inferior than that of DCs. However, studies
suggest that there exists a complicated interplay
between macrophages and DCs in the process and
presentation of Ag. For instance, upon dead cell
accumulation in vivo, macrophages transfer
phagocytosed Ag to DCs via exosomes for potent

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antigen presentation and efficient T‐cell activation
[181]. In addition, despite inefficient cellular uptake of
Listeria monocytogenes (Lm), DCs are capable of
taking up microparticles (MPs) released by
Lm-infected macrophages. These MPs transport Lm
Ag to DCs for presentation, propagating DC-elicited
protective immunity against Lm infection [175].
Similarly, macrophages act as transmitters to convey
Ag for presentation by DCs in response to the
invasion of other pathogens such as mycobacterium
[176, 177] and salmonella [178]. Moreover, it is found
that infected macrophages secrete EVs containing
Cdc42 (a protein responsible for increased cellular
endocytic activity) to enhance the cellular uptake of
recipient cells [179], which may further facilitate the
antigenic cross-talk between macrophages and DCs.
B cells, macrophages and DCs
A successful elicitation of the humoral immunity
depends primarily on the close antigenic interaction
among B cells, macrophages and DCs. In both LNs
and spleen, the maturation and native antigen
presentation of B cells requires the support from
follicular dendritic cells (FDCs) and CD169+
subcapsular sinus (SCS) macrophages [180].
Specifically, at the T-B border, SCS macrophages
display Ag including processed viral particles,
vaccine particles and immune complexes [181, 182] to
both cognate and non-cognate B cells via TNTs-like
cellular protrusions that extend into follicles. SCS
macrophages-mediated Ag recognition by cognate B
Figure 3. Close intercommunication among B cells, macrophages and DCs in the LNs.
Peripheral migratory conventional DC1 and DC2 (i.e., mcDC1 and mcDC2)
move back to the draining LNs via afferent lymphatics and transfer Ag (including viruses, particulate Ag and immune complexes) to CD169+
subcapsular sinus (SCS) macrophages
that line the follicle-proximal side of the SCS. Then, these SCS macrophages display Ag to follicular B cells via cellular protrusions, and follicul
ar DCs (FDCs) located therein
engage in reciprocal Ag sharing with B cells for elicitation of germinal center reactions. Afterwards, mcDC1 and mcDC2 pass through the T-
B boundary and enter the T
cell-localized medullary zone to share Ag with resident conventional DCs (rcDCs) for efficient activation of immune responses.

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cells through B cell antigen receptors (BCRs) initiates
the early activation and the subsequent migration to
T-B border of B cells [183]. Meanwhile, immune
complexes are transferred from SCS macrophages to
non-cognate B cells, and then ferried into the follicle
for deposition on FDCs [183, 184]. Then, FDCs retain
native Ag for prolonged presentation to B cells that
evokes the germinal center reactions and promotes
the maturation of effector and memory B cells.
Notably, evidence suggests that in the lymphoid
germinal center, direct intercellular communication
through gap junctions is involved in FDCs-FDCs and
FDCs-B cells interaction, in which multiple signal
molecules and Ag fragments/complexes can be
shared [89]. On the other hand, there is mounting
evidence that both migratory and resident cDCs may
encounter cognate B cells at the T-B border and
contribute to their early initiation [180, 185]. Besides,
Lectin-like oxidized low-density lipoprotein
receptor-1 (LOX-1) signaling on DCs promotes B cell
differentiation into class-switched plasmablasts and
facilitates their exit from germinal center and
migration towards local mucosa and skin [186].
Furthermore, result illustrates that Ag acquired by B
cells through BCRs can be specifically transferred to
B220+ macrophages through direct cell-cell contact,
which enables the macrophages to activate CD4+ T
cells [187].
From non-APCs to APCs
Given the homologous expression of MHC class
I molecules by all nucleated cells, non-APCs can also
serve as Ag donor cells to APCs, especially to DCs,
including malignant/transformed cells, vaccinated
muscle cells and KCs, and even harmless commensal
bacteria. Antigen transfer from non-APCs to APCs
may promote the immune response against the “non-
self” or facilitate the spread of invasive pathogens.
Tumor cells and DCs
Tumor infiltrating DCs assume different
functional states that affect the antigen transfer and
overall antitumor immunity (Figure 4A). In the TME,
interferon regulatory factor 8 (IRF8)-dependent
CD103+ cDC1 (CD141+ cDC1 in human) are the only
APCs that can cross present tumor rejection Ags for
activation of specific CTLs [23], which are sparsely
distributed and frequently threatened by the hostile
immunosuppressive environment [188]. In this
situation, antigen transfer, especially cross dressing
(i.e., p-MHCs transfer), from tumor cells to cDC1s
stands as an efficient means of Ag presentation and
reactive T cell activation [44, 189]. On the other hand,
cDC2 is developmentally driven by interferon
regulatory factor 4 (IRF4) and highly specialized in
MHC II-restricted presentation [29]. Recently, Duong
et al. [190] investigated the transcriptional profiles of
intra-tumoral DCs within regressor tumors and
identified an activation state of CD11b+ cDC2 with
interferon-stimulated gene signatures. Stimulated by
exogenous IFN-β, these cDC2 acquired and presented
intact tumor-derived p-MHC class I complexes to
induce CD8+ T cell-involved antitumor immunity
against progressor tumors in mice lacking cDC1 [188,
190]. Moreover, Bonaccorsi et al. [191] identified that
pDCs, although inefficient in internalizing cell
membrane fragments by phagocytosis, were able to
acquire membrane patches and associated molecules
Figure 4. Antigen transfer from non-APCs to APCs in the context of anti-cancer/-infection immunity. (A)
Tumor cells serve as the largest Ag reservoir for
migratory conventional DCs (mcDCs), plasmacytoid DCs (pDCs) and macrophages. Ag is transferred from tumor cells to these APCs through both contact de
pendent (i.e.,
trogocytosis, gap junctions and TNTs) and independent (i.e., EVs) pathways, leading to activation and expansion of T cells in situ or in the dLNs. (B)
Hepatitis C virus
(HCV)-infected parenchymal hepatocytes release virus RNA and protein Ag
through both contact dependent and independent pathways for activation of Kupffer cells and pDCs
against virus invasion. TAAs, tumor associated antigens; TSAs, tumor specific antigens.

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from cancer cells of different histotypes in a cell-to-
cell contact-dependent manner that closely resembled
“trogocytosis”. As a result, tumor cell-derived Ag was
displayed by pDCs and recognized by specific CD8+ T
cells to promote anti-tumor cellular immune
response.
Virus infected cells and DCs
During hepatitis C virus (HCV) infection,
exosomes mediate the intercellular transfer of
immunostimulatory HCV RNA from infected cells to
neighboring non-infectible pDCs to trigger the
generation of type I IFN [192] (Figure 4B). Both
HCV-infected cells and purified HCV RNA-packaged
exosomes are sufficient to activate pDCs without
infecting them. Notably, the exosomal viral RNA
transfer is dependent on active viral replication, direct
cell-cell contact and TLR 7 signaling [193].
Nevertheless, such exosome-mediated transfer of
viral RNA may enhance virus clearance by activating
Kupffer cells and pDCs or promote virus infection by
delivering infectious viral genomes to cells that are
permissive for viral replication.
Vaccinated somatic cells and DCs
To improve the efficacy of protein- or nucleic
acid- based vaccines, substantial efforts have been
paid to promote the site-specific accumulation of
vaccine components in SLOs, and even in APCs
[194-199], which increases the availability of vaccine
Ag by DCs to amplify specific immune response and
establish a durable memory. However, a targeted
delivery of vaccine preparation proposes great
demands for its physiochemical properties (e.g.,
particle size, potential and surface modification) and
route of administration [200, 201]. Moreover,
compared to professional APCs that have a limited
cell abundance in different vaccination sites, somatic
cells with larger quantity and widespread distribution
display higher competence in messenger RNA
(mRNA)-transfection and protein-uptake, which may
impact the magnitude and duration of specific
immunoresponse by transferring Ag to nearby APCs
(specific mechanisms of Ag transfer need to be further
identified) [2]. Indeed, most somatic cells are
biologically equipped with abundant cytoplasmic free
ribosomes (such as KCs and muscle cells) or rough
endoplasmic reticulum-attached ribosomes (such as
hepatocytes and fibroblasts) to support their antigenic
communication with surrounding DCs [33]. For
example, KCs actively transfer Ag, including
Ag-encoding mRNA [161] and protein [162], to the
skin-resident LCs mainly in a contact-dependent
fashion, impacting the efficacy and safety of
transdermal- and intramuscular- injected vaccines.
Commensal bacteria and DCs
It is reported that several bacteria participate in
tumor immunosurveillance and antitumor immune
response. Rong et al. [202] studied the bacteria-
reactive CD8+ T cell response in HBV-associated
hepatocellular carcinoma patients and found that
circulating CD8+ T cells displayed remarkable
enhanced immune responses against a series of
commensals and bacteria, including Escherichia coli
(E. coli), Enterococcus faecium, Bifidobacterium
longum, Bacteroides fragilis, and Enterococcus hirae.
And the ratio of CD8+ T cell-to-Foxp3+ Treg was
positively correlated with the proportion of
Bifidobacterium longum-reactive and Enterococcus
hirae-specific CD8+ T cells, whereas the frequency of
PD-1+ CD8+ T cells was negatively correlated with the
frequency of Enterococcus hirae-specific CD8+ T cells.
Moreover, these bacteria-reactive responses were
MHC class I-restricted and dependent on the presence
of APCs, indicating that certain commensal bacteria
might act as Ag mediators between cancer cells and
APCs to increase the proportion and viability of
tumor-reactive IFNγ+ T cells [202], which is also
observed in MC38 colon cancer, MCA-205 sarcoma
and RET melanoma [203-205].
Vaccine effect of antigen transfer:
immune amplification or tolerance
Antigen transfer plays an important role in
coordinating immune amplification and tolerance.
When the receptor cells are tolerogenic DCs,
immature DCs, some pDCs and even certain types of
non-APCs [110, 138, 165, 206-208], antigen transfer
may promote the expansion of immunosuppressive
Tregs/MDSCs and even induce the apoptosis of
specific T cells, leading to tolerance [47]. Immune
tolerance is fundamental to the maintenance of
homeostasis. For example, antigen transfer from
mTECs to DCs in the thymus enables the deletion of
self-reactive T cells and promotes the establishment of
central tolerance [118-120]. In patients with
autoimmune diseases, harmless Ag (e.g., autoantigens
and dietary proteins) are recognized as pathogenic
Ag, which consequently causes local/systemic
inflammatory responses that are harmful and even
fatal. In this situation, antigen transfer that induces
tolerance to specific Ag may limit autoimmune
responses and help restore homeostasis [146, 209,
210]. On the other hand, antigen transfer to mature
APCs, especially DCs, may facilitate the access and
presentation of Ag that contributes to a more efficient
and versatile elicitation of the adaptive immunity [1,
48, 55, 134, 190, 211], which is frequently used to
enhance the preventive and therapeutic effects of

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vaccines [26].
Vaccines are powerful weapons against
pathogenic evasion [26] and tumor progression [212-
216], which elicit specific T/B lymphocyte-mediated
effector and memory immune responses upon single
or repeated inoculation. Considering the efficacy and
biosafety, most recently licensed vaccines are typically
protein/peptide-based subunit vaccines that usually
used in combination with adjuvants, nucleic
acid-based vaccines (especially mRNA vaccine)
[217-219], and DCs-based vaccines [220, 221]. And
transcutaneous local injection is the most applied
route of administration for these vaccines [222],
including:
1) Intradermal injection (i.d.), which is most
frequently used for the inoculation of bacillus
Calmette-Guérin (BCG), rabies and smallpox vaccines
[223] for its little invasiveness, avoided drug
degradation in the gastrointestinal tract, and escaped
hepatic first-pass effect. Vertebrate skin comprises
epidermis and dermis. Epidermis is composed of
abundant KCs and few melanocytes and LCs. In
contrast, dermis is rich in collagen and elastin fibers
but low in cell density. Dermal APCs (such as cDCs,
mo-DCs, LCs and macrophages) [224] and lymphatic
system facilitate a quick and effective initiation of
immune response, conferring dermis a highly
immunocompetent site for vaccine delivery [225, 226].
2) Subcutaneous injection (s.c.), that is most
suitable for the administration of live-attenuated
vaccines against polio, measles, mumps, rubella and
yellow fever. Subcutaneous compartments
incorporate blood vessels, nerves, loose connective
tissue and adipose tissues, where fibroblast, mast cell
and macrophage are most abundant. Subcutaneous
drainage system is underdeveloped, which prolongs
the in-situ Ag dwelling and serves as Ag reservoirs.
3) Intramuscular injection (i.m.). As the most
commonly used route of delivery for licensed vaccine,
especially inactivated vaccines against hepatitis A/B
(HepA/B), HPV, influenza, and the currently
prevalent severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), i.m. is easy to perform
and generally well tolerated, with a low risk for
adverse reactions [212-214, 227]. Muscle tissue is
composed primarily of myocytes, with few APCs,
blood vessels and nerves. Therefore, higher dosage,
adjuvant-incorporation, and multiple administration
is usually recommended for eliciting an expected
immunoprotection [228].
In addition, intravenous (i.v.) and intranodal
(i.n.) injection have also been studied [229]. However,
their feasibility and safety needs to be further
optimized before putting into clinical use [230]. It’s
worth noting that a long-term persistence of
immunogens/immunomodulators or sustained
expression of vaccine products was observed at the
site of delivery following i.d., s.c., and i.m. (superficial
injection). Meanwhile, upon i.v., i.m. (deep injection),
and intraperitoneal injection (i.p.), significant
antigenic signal was detected in the liver early post
administration [231, 232], suggesting that the
biodistribution of vaccine is route-dependent, and
liver may be an important anatomical compartment
for mounting immunoreactions.
Antigen transfer takes place after vaccine
inoculation, which is primarily grouped into the
following categories according to the type and tissue
distribution of vaccine (Table 2): 1) Antigen (such as
Ag-encoding nucleic acids, Ag peptides/fragments,
intact Ag proteins, particulate Ag, immune complex
and functional p-MHCs) transfer from vaccinated
APCs and/or non-APCs to neighboring DCs at site of
administration in the context of protein/peptide-
based vaccines (Figure 5A) and nucleic acid-based
vaccines (Figure 5B); 2) Antigen transfer from
Ag-pulsed DCs to nearby APCs including LCs, cDCs
and macrophages at vaccine inoculation site in terms
of DCs-based vaccines (Figure 5C); and 3) Antigen
sharing from Ag-laden DCs to SCS macrophages, B
cells, FDCs and cDCs at the dLNs to activate germinal
center reactions.
Protein-based vaccines
Increasing studies suggest that the efficiency of T
cell-mediated adaptive immunity against peripheral
infections and particulate vaccine systems (such as
nanoparticles, microparticles and adjuvant-
formulated proteins) depends heavily on the ability of
LNs-homing and Ag presentation by peripheral DCs
[233]. In addition, it seems that most soluble Ags
cannot penetrate into the paracortex and cortex of
LNs, which directly limits the Ag accessibility of
LNs-resident DCs [237, 238]. At the same time,
anatomic studies indicate that Ag diffused into the
LNs in a size-dependent manner seems to accumulate
only at the proximal ends near the afferent lymphatic
vessels, whereas Ag carried by migratory DCs
penetrates deep into the medullary zone [128]. On the
other hand, vaccine Ag transferred from vaccinated
muscle cells, KCs, fibroblasts and other tissue cells to
skin-resident DCs in the epidermis and dermis is
reported to facilitate a durable immune response
under limited dosage of vaccine inoculation [32, 33]
(Figure 6A). Therefore, antigen transfer to DCs is of
physiological and clinical significance.

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5903
Table 2. Antigen transfer and its immunological effects by different types of vaccine
Vaccine type
Vaccine component
Administration
route
Major Ag donor cells
Major Ag receptor cells
Immunological outcome
Ref.
Protein-based vaccine
Protein
Multivalent HPV protein Ag and
adjuvant AS04
i.m.
Muscle cells and
skin-resident DCs,
respectively
Skin-resident DCs and
LNs-resident DCs,
respectively
Prevent HPV induced infections and
cancers
[212-214]
Protein
5-20 recombinant/fusion tumor
neoantigens
s.c.
KCs and skin-resident
DCs, respectively
Skin-resident DCs and
LNs-resident DCs,
respectively
71.4 % of cancer patients are under
control with specific CTL response
elicited
[236]
Protein
TAAs (HER-2) and
immunostimulatory molecules
modified plasma membrane
vesicles (PMVs)
s.c.
Breast cancer cells
DCs in subcutaneous
compartment and LNs
Induce both cellular and humoral
immunity against HER-2-
expressing tumor cells
[241]
Protein
M2e-displaying outer membrane
vesicles (OMVs)
s.c.
Escherichia coli
Skin somatic cells and
DCs
Initiate specific humoral immunity
against influenza A (H1N1)
[240]
Protein
Oligodendrocyte-derived EVs
containing multiple myelin Ags
i.v.
Oligodendrocyte,
monocyte, cDCs
mo-DCs
Induce immunosuppressive
monocytes and apoptosis of
autoreactive CD4+ T cells in several
autoimmune encephalomyelitis
models
[283]
Protein
OVA
s.c.
Skin somatic cells and
CCR9+ pDCs,
respectively
CCR9+ pDCs and thymus
cDCs, respectively
Induce pDCs-mediated thymic central
tolerance
[249]
Nucleic acid-based vaccine
pDNA
OVA pDNA
i.m.
KCs
CD103
+
/CD8α
+
DCs
Activate OVA-specific CD8
+
T cells
[49]
pDNA
Bacillus anthracis protective
antigen domain 4 (PA-D4)
pDNA
i.d. by
electroporation
KCs
Skin-resident DCs
Induce potent Anthrax-associated
humoral immune response
[284]
pDNA
OVA pDNA and GM-CSF
-loaded mesoporous silica
microrods (MSRs)
s.c.
KCs and migratory
DCs, respectively
Skin-resident DCs and
LNs-resident DCs,
respectively
Elicit OVA-specific CTL response, Th1
humoral response and CD8+ effector
and memory T cell responses
[285]
mRNA
Influenza A mRNA delivered by
Lipofectamine 2000
i.m.
Muscle cells
mo-DCs
Cross prime CD8
+
T cells in vivo
[33]
mRNA
Protamine mRNA
i.d.
KCs and migratory
DCs, respectively
Migratory DCs and
LNs-resident DCs,
respectively
Induce functional Ags in the dLNs
and massive activation of T cells
[32]
DCs-based vaccine
mo-DCs
Mo-DCs loaded with both
keyhole limpet hemocyanin
(KLH) and TAA
i.d., i.n.
mo-DCs
CD163+ macrophages and
LNs-resident DCs
Induce Ag-specific immune response
in patients with melanoma
[273]
mo-DCs
In vivo activated mo-DCs
s.c.
mo-DCs
LNs-resident CD8α
+
DCs
Activate B16-OVA specific CD8
+
T cell
immune response
[279]
mo-DCs
Tumor whole cell lysate-pulsed
mo-DCs
i.d.
mo-DCs
Possibly DCs and
macrophages in the dLNs
and vaccine injection site
Nearly half of the patients generate
specific immune responses against
glioblastoma, with survival time
prolonged
[268, 277]
mo-DCs
Tumor whole cell lysate-pulsed
mo-DCs
s.c.
mo-DCs
Possibly DCs and
macrophages in LNs and
vaccine injection site
Induce renal cell cancer-specific Th1
immune response
[286]
cDC2 and
pDCs
Three TAAs/mRNA-pulsed
cDC2 and pDCs
i.d.
cDC2 and pDCs
LNs-resident DCs
Increase metastatic
castration-resistant prostate cancer
(mCRPC) reactive IFN-γ
+
CTLs
[276]
cDC2
TAAs (gp100 and tyrosinase)
-pulsed cDC2
i.d.
cDC2
LNs-resident DCs
Prolong progression free survival in
some melanoma patients
[274]
pDCs
TAAs (gp100 and tyrosinase)
-pulsed pDCs
intra-LN
pDCs
LNs-resident DCs
Prolong the survival of melanoma
patients with 1-2 years
[275]
pDCs
Peripheral Ag (OVA) -loaded
pDCs
i.v.
CCR9
+
pDCs
Thymus-resident cDCs
Induce central tolerance
[249]
The bivalent (2vHPV, Cervarix), quadrivalent
(4vHPV, Gardasil) and nine-valent (9vHPV, Gardasil
9) human papillomavirus (HPV) vaccines are
primarily composed of noninfectious virus-like
particles (VLP) that display potent protection against
cervical infections caused by HPV, condylomas and
some HPV-related cancers [212-214, 234, 235].
Recently, accumulating evidence indicates that
muscle cells at site of injection may act as Ag
reservoirs/donors for DCs during i.m. administration
to promote the establishment of a sustained anti-viral
effector and memory immune defense [236-239].
Antigen transfer is also involved in other
protein-based vaccines and contributes to an efficient
disease prevention and control. Rappazzo et al. [240]
reported influenza vaccines based on bacteria-derived
outer membrane vesicles (OMVs) and ectodomain of
the influenza M2 protein (M2e). Briefly, OMVs were
engineered to display M2e by transforming E. coli
with a plasmid encoding the transmembrane protein
ClyA followed by the Ag of interest, which elicited
high IgG titers and protects against lethal doses of the
mouse-adapted H1N1 influenza strain PR8 in BALB/c
mice, probably due to the OMVs-mediated Ag
transfer to APCs in vivo.

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Figure 5. Characteristics of the currently most licensed three vaccine types. (A) Protein-based vaccines. Widely used in clinical practice, these vaccines incorporate
disease-associated Ag protein/peptide (usually insufficient in immunogenicity) and adjuvants (such as alum and Freund's adjuvants) and are mainly administrated via i.m., s.c., i.d.,
and i.n. (less adopted). After administration, Ag is transferred from vaccinated somatic cells (such as muscle cells, keratinocytes and fibroblasts) and APCs (such as rDCs, LCs and
macrophages) to DCs at the injection site to amplify immune responses for disease prevention and treatment. (B) Nucleic acid-based vaccines. These vaccines contain
Ag-encoding mRNA or plasmid DNA (pDNA) with self-adjuvant effects and are inoculated mainly by i.d., s.c. and i.m. After injection, vaccine particles/naked nucleic acids are
internalized, translated, processed and presented by local somatic cells and APCs, or undergo Ag (the original Ag, translated/process/displayed Ag fragments or Ag complexes)
transfer to DCs, serving as prophylactic and therapeutic agents. (C) DC-based vaccines. Primarily administrated through i.d., s.c., i.m., i.v. and i.n. (less adopted), these vaccines
are mainly composed of ex vivo-cultured mo-DCs derived from autologous/allogeneic mononuclear progenitor cells or endogenous cDCs/pDCs isolated and enriched from blood
to provide an individualized therapeutic effect. These DCs are pulsed with Ag and adjuvant prior to administration, and Ag-laden DCs can also transfer Ag to nearby APCs in vivo.
i.d.: intradermal injection; i.m.: intramuscular injection; i.n.: intranodal injection; i.v.: intravenous injection; s.c.: subcutaneous injection; TAA: tumor associated antigen; TSA:
tumor specific antigen.
Figure 6. Antigen transfer in protein-based vaccines and nucleic acid-based vaccines. (A) After local administration of protein-based vaccines, Ag is captured,
processed, presented and/or intercellularly shared by epidermal LCs and keratinocytes (KCs). Subsequently, activated Langerhans cells (LCs) migrate to the dermis for activation
of migratory conventional DCs (mcDC1 and mcDC2) via antigen transfer. Meanwhile, fibroblasts in the dermis may also internalized and transfer Ag to DCs. Activated dermal
cDCs and LCs then homing to the dLNs in a CCR7-dependent manner to induce immune response. Meanwhile, free Ag particles may also diffuse into the dLNs in a
size-dependent manner to directly activate adaptive immunity. (B) Nucleic acid-based vaccines are locally administrated to be internalized and transfected by LCs, KCs and
fibroblasts. Subsequently, these vaccinated cells may transfer Ag to skin DCs for dLNs-homing and immune activation. Similarly, nucleic acids and expressed Ag may directly drain
toward the dLNs to induce immune response. i.d., intradermal injection; s.c., subcutaneous injection; i.m., intramuscular injection; i.n., intranodal injection.

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Patel et al. [241] reported a biocompatible
particulate protein delivery system that may exploit
the phenomenon of Ag transfer from tumor cells to
DCs for improved immunization. Briefly, plasma
membrane vesicles (PMVs) are prepared from
biological materials (such as cultured cells and
isolated tissues) and surface-modified by
glycosylphosphatidylinositol (GPI)-anchored TAAs
(breast cancer Ag: human epidermal growth factor
receptor-2 (HER-2) in this work) and immuno-
stimulatory molecules (such as interleukin (IL)-12 and
B7-1), which induced both cellular and humoral
immunity against a HER-2-expressing tumor cell
challenge along with delayed tumor growth and
partial regression of established tumors.
DCs-derived exosomes (Dex) are loaded with
costimulatory molecules, functional p-MHCs and
other immune cell-interacting elements, and are
especially enriched in p-MHC class II complexes, by
10-100-fold that of DCs, which might lead to a more
efficient Ag transfer to other DCs and remarkable
immunological impacts [242]. It should be noted that
the immune effects (i.e., stimulation or inhibition) and
biological activity of Dex depend on the activation
status of donor DCs and the follow-up artificial
manipulation of the isolated endosomes. For instance,
compared with that from immature DCs, Dex from
mature murine DCs are enriched in MHC class II,
costimulatory B7.2, intercellular adhesion molecule 1
(ICAM-1) and depleted in milk fat globule-epidermal
growth factor-factor VIII (MFG-E8), which are 50- to
100-fold more potent in functional T-cell activation
both in vitro and in vivo [243]. And the involvement of
exosomes in the induction of host defense and
immune evasion has been reviewed by Schorey et al.
[244] in detail. Indeed, with advances in molecular
and cellular biology, such cell-free multifunctional
protein delivery platform might have widespread
applications in mediating antigen transfer for a
desired immune regulation [245-248].
As mentioned before, antigen transfer might also
induce immune tolerance and dampen the protective
effect of protein-based vaccines. Hadeiba et al. [249]
found that peripheral pDCs engulfed subcutaneously
injected exogenous Ag in the absence of TLR signals,
and subsequently migrated to the thymus in a
CCR9-dependent manner to delete Ag-reactive
thymocytes and induce immune tolerance.
Specifically, pDCs themselves fail to make physical
contacts with CD4+ T cells, and are incapable of
directly inducing T cell proliferation. Nonetheless,
pDCs transport and transfer Ag to thymic APCs to
abort the activation and clonal expansion of cognate
CD4+ T cells, inducing Ag-specific systemic tolerance
[208]. However, the mechanistic details of such Ag
transfer in tolerogenic T cell induction needs further
exploration. In addition, given that co-stimulatory
membrane molecules and immunostimulatory
soluble molecules are low-expressed in most
non-APCs, the direct transfer of functional p-MHC
class I complexes from Ag-pulsed non-APCs to
immature DCs may sometimes induce T-cell tolerance
and/or exhaustion due to insufficient costimulatory
signals [2, 59, 60, 110].
Nucleic acid-based vaccines
Compared to protein/peptide-based subunit
vaccines that are generally inadequate in
immunogenicity, nucleic acid-based vaccines have
self-adjuvant effect and can act as pathogen-
associated molecular patterns (PAMPs) to stimulate
pattern-recognition receptors (PRRs, such as TLR-3/
-7/-8/-9) for amplified immune responses [32, 250],
which have emerged as promising vaccine platforms
in anti-cancer and anti-viral immunotherapy [251,
252]. And antigen transfer during the inoculation of
nucleic acid-based vaccines is increasingly gaining
attention for its potential clinical benefits (Figure 6B).
Considering the great discrepancy in lymphatic
draining system and cell abundance of different
vaccination sites, the administration route and
delivery vehicle of the nucleic acid of interest
significantly shapes the efficiency and duration of
vaccine responses. DNA- and mRNA-based vaccines
are commonly delivered via i.d. [253], i.m. [254] and
s.c. [255], or through the less adopted i.n. [256], i.v.
[257], intra-tumoral injection [258], intra-splenic
injection [259], and intranasal administration [260].
After administration, Ag-encoding nucleic acids
are directly captured, processed and presented by
DCs through MHC class I-biased pathway, or
indirectly transferred to DCs from transfected somatic
cells in the form of exogenous protein/peptide to
induce MHC class II-preferred Ag presentation. In
addition, it is reported that pDNA-vaccinated somatic
cells may 1) present associated p-MHC class I
complexes on the cell surface to be recognized and
even cytolyzed by cognate CD8+ T cells [261]; or 2) be
phagocytized by DCs for further process and
presentation [262]. For example, Li et al. [49] found
that following vaccination with ovalbumin-encoding
pDNA (OVA-pDNA, i.m.), CD103+/CD8α+ DCs
obtain antigenic information from transfected KCs via
cross dressing to efficiently activate both naïve and
memory CD8+ T cells. Similarly, after administration,
mRNA vaccines are extensively internalized and
expressed by muscle cells and KCs, and the resultant
Ag protein/peptide can be transferred to nearby
APCs for CD8+ T cell activation and immune
amplification [32, 33].

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5906
DCs-based vaccines
The adoptive transfer of ex vivo-activated DCs
has been widely recognized with good biosafety and
sufficient efficacy in clinical anti-tumor therapy [263].
Briefly, CD34+ bone marrow progenitors or CD14+
peripheral blood monocytes are isolated and
stimulated with granulocyte-macrophage colony
stimulating factor (GM-CSF) and IL-4 in vitro to
generate mo-DCs [264, 265]. Then, the resultant
mo-DCs are pulsed with 1) TAAs and/or TSAs [266,
267]; 2) tumor whole cell lysates [268]; or 3) tumor-
derived EVs [269, 270], and concurrently stimulated
with adjuvants for maturation [271]. However, the
clinical efficacy of mo-DCs-based vaccine is greatly
limited by its inferior ability of CCR7-dependent LNs
homing and Ag cross presentation [272]. As a result, a
large proportion of mo-DCs remained at the site of
administration, lost viability and are eliminated by
phagocytes [273]. In this consideration, some current
clinical trials have used enriched cDCs and pDCs that
directly collected from the peripheral blood and
activated in vitro before administration, which might
have broader immunotherapeutic applications as
these DCs subsets display superior LNs homing and
T-cell cross priming [274-276].
Nevertheless, multiple clinical phase II and
phase III studies have shown that the less mobilized
mo-DCs are sufficient in eliciting potent immune
responses in cancer therapy [268, 276-278], which may
attribute to the antigen transfer from mo-DCs to other
APCs both at the site of injection and the dLNs [29,
273, 279] (Figure 7). For example, Huang et al. [174]
found that even undifferentiated monocytes loaded
with Ag protein or peptide induced robust CD8+ T cell
responses by Ag transfer to endogenous splenic CD8+
DCs in a cell-to-cell contact-dependent fashion and
through Cx43-mediated intercellular gap junctions.
On the other hand, DCs retain at the injection site may
transfer Ag to tissue-resident LCs or circulating cDCs
through multiple contact- and non-contact-
dependent pathways including EVs and trogocytosis
to sensitize the immune system for specific activation
[72]. Meanwhile, dead cells, cell derbies and apoptotic
bodies of those DCs can be phagocytized by
infiltrating CD163+ macrophages as an approach of
passive Ag transfer. Consequently, Ag-laden
macrophages migrate to the liver for further Ag
sharing and T-/B-cell activation [273]. In short,
intercellular antigen transfer during the
administration of DCs-based vaccines may serve as an
efficacious strategy to amplify immune response.
Figure 7. Antigen transfer in DC-based vaccines. After local injection, adoptively transferred DCs (as represented by monocyte-derived DCs (mo-DCs)) transfer Ag to
Langerhans cells (LCs) in the epidermis (1) and migratory conventional DCs (mcDCs) in the dermis (2). Then, part of Ag-loaded mo-DCs, LCs and mcDCs migrate to the dLNs
in a CCR7-dependent manner to activate adaptive immune responses (3-1). In addition, mo-DCs that undergo apoptosis in situ and their apoptotic bodies are mainly
phagocytosed by macrophages (3-2) and transported to the liver for immune activation (4).

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Conclusions and Discussion
In this review, mainly focused on DCs-based
antigen receptors, we summarize the recent
understanding of antigen transfer and its impact on
immune amplification and tolerance. We conclude
that antigen transfer plays an important role in
coordinating immune responses against the invasion
of the “non-self”. Therefore, appropriately
manipulating antigen transfer may promote the
preventive and/or therapeutic effects of vaccines,
which depends heavily on a rational design of the
vaccine component and administration route.
Meanwhile, undesired antigen transfer may induce
tolerance or cause allergy, graft rejection and
autoimmune diseases. In these regards, reasonable
intervention that blocks or disturbs antigen transfer is
needed.
Of note, antigen transfer-associated immune
amplification and tolerance can sometimes be
interconvertible. In fact, persistent and/or
excessively/insufficiently-dosed Ag stimulation may
induce a tolerogenic phenotype of DCs that leads to
vaccine failure. To avoid the induction of unwanted
tolerance to an antigen of interest, 1) adjuvants that
facilitate the recruitment, mobilization, and
maturation of DCs can be supplemented; 2) the route
of vaccine delivery that determines the participants of
antigen transfer needs further consideration; 3) the
dose and type (i.e., protein-, nucleic acid-, or cells-
based vaccines) of vaccine should be carefully selected
as different mechanisms of antigen transfer may be
involved.
Up to now, the key steps and mediators directing
the intercellular antigen transfer remain obscure, and
the immunological and pathological consequences of
antigen transfer in different biological processes
require further exploration. Therefore, more efforts
are needed for proper regulation over the mode, site
and participant of antigen transfer that might
contribute to a more satisfactory immune outcome.
Abbreviations
Ag: antigen; p-MHCs: peptide-MHC complexes;
SLOs: secondary lymphoid organs; TNTs: tunnel
nanotubes; EVs: extracellular vesicles; DCs: dendritic
cells; APCs: antigen-presenting cells; Tregs:
regulatory T cells; cDCs: conventional DCs; LCs:
Langerhans cells; pDCs: plasmacytoid DCs; mo-DCs:
monocyte-derived DCs; LNs: lymph nodes; PPs:
Peyer’s patches; KCs: keratinocytes; HSV: herpes
simplex virus; EBV: Epstein-Barr virus; CTL: cytotoxic
T lymphocyte; TAAs: tumor-associated antigens;
TSAs: tumor-specific antigens; HIV: human
immunodeficiency virus; HLA-G: human leukocyte
antigen-G; MDSCs: myeloid-derived suppressive
cells; FDCs: follicular DCs; Cx43: Connexin 43; dLNs:
draining lymph nodes; F-actin: filamentous actin;
CCR7: chemokine receptor 7; MVEs: multivesicular
endosomes; EVIR: extracellular vesicles-internalizing
receptors; mTECs: medullary thymic epithelial cells;
AIRE: autoimmune regulator; SCS: subcapsular sinus;
SFB: Segmented filamentous bacteria; IECs: intestinal
epithelial cells; Th17: T helper type 17; Mφ:
macrophages; MCs: Mast cells; MCGs: mast cell
granules; VPS4: vacuolar protein sorting 4; AD: atopic
dermatitis; Th2: T helper type 2; HDM: house dust
mite; DAMPs: danger-associated molecular patterns;
TLRs: Toll-like receptors; SLE: systemic lupus
erythematosus; mtDNA: mitochondrial DNA; PD-L1:
programmed death-ligand 1; CLEC9A: C-type
lectin-like receptor 9A; EVIR: extracellular
vesicle-internalizing receptor; NK: natural killer;
CEA: carcinoembryonic antigen; Th1: T helper type 1;
NIPCs: natural interferon producing cells; IFN: type I
Interferon; Lm: Listeria monocytogenes; MPs:
microparticles; BCRs: B cell antigen receptors; LOX-1:
Lectin-like oxidized low-density lipoprotein
receptor-1; mcDCs: migratory conventional DCs;
rcDCs: resident conventional DCs; IRF8: interferon
regulatory factor 8; IRF4: interferon regulatory factor
4; HCV: hepatitis C virus; mRNA: messenger RNA; E.
coli: Escherichia coli; HepA/B: hepatitis A/B;
SARS-CoV-2: severe acute respiratory syndrome
coronavirus 2; pDNA: plasmid DNA; HPV: human
papillomavirus; VLP: virus-like particles; OMVs:
outer membrane vesicles; M2e: influenza M2 protein;
PMVs: plasma membrane vesicles; GPI: glycosyl-
phosphatidylinositol; HER-2: human epidermal
growth factor receptor-2; IL: interleukin; Dex:
DCs-derived exosomes; ICAM-1: intercellular
adhesion molecule 1; PAMPs: pathogen-associated
molecular patterns; PRRs: pattern-recognition
receptors; GM-CSF: granulocyte-macrophage colony
stimulating factor.
Acknowledgements
This work was supported by the National
Nature Science Foundation of China (81573365,
82003667).
Author Contributions
Y. Shi & Y. Lu: Conceptualization, Visualization,
Writing-original draft, and Writing-review & editing.
J. You: Supervision, Funding acquisition and
Writing-review & editing.
Competing Interests
The authors have declared that no competing
interest exists.

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5908
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