Dendritic Cells in Transplantation and
James W. Young,1Miriam Merad,2Derek N. J. Hart3
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University,
New York, New York USA;2Department of Gene and Cell Medicine, Mt Sinai School of Medicine, New York,
New York USA; and3Mater Medical Research Institute, University of Queensland School of Medicine, Brisbane,
Correspondence and reprint requests: James W. Young, MD, Memorial Sloan-Kettering Cancer Center,
1275 York Avenue, New York, NY 10021(e-mail: firstname.lastname@example.org).
Dendritic cells (DCs) are specialized, bone marrow–derived leukocytes critical to the onset of both innate and
adaptive immunity. The divisions of labor among distinct human DC subtypes achieve the most effective
balance between steady-state tolerance and the induction of innate and adaptive immunity against pathogens,
tumors, and other insults. Maintenance of tolerance in the steady state is an active process involving resting or
semimature DCs. Breakdowns in this homeostasis can result in autoimmunity. Perturbation of the steady state
should first lead to the onset of innate immunity mediated by rapid responders in the form of plasmacytoid and
monocyte-derived DC stimulators and natural killer (NK) and NK T-cell responders. These innate effectors
then provide additional inflammatory cytokines, including interferon-?, which support the activation and
maturation of resident and circulating populations of DCs. These are critical to the onset and expansion of
adaptive immunity, including Th1, Th2, and cytotoxic T-lymphocyte responses. Rodent models are now
revealing important data about distinct DC precursors, homeostasis of tissue-resident DCs, and DC turnover
in response to inflammation and pathological conditions like graft-versus-host disease. The use of defined DC
subtypes to stimulate both innate and adaptive immunity, either in combination or in a prime-boost vaccine
sequence, may prove most useful clinically by harnessing both effector cell compartments.
© 2007 American Society for Blood and Marrow Transplantation
DENDRITIC CELLS AT THE CROSSROADS OF INNATE
AND ADAPTIVE IMMUNITY
Human Dendritic Cells: Distinct Subsets and
From the initial description of dendritic cells
(DCs) in human skin  to the discovery of DCs in
mouse spleen almost a century later , progress in
the study of DC biology exploded in the 1990s. In-
vestigators developed cytokine-driven methods for ex-
panding and differentiating DCs ex vivo in both
mouse and human systems, and further refinements
continue to emerge. For the first time, sufficient num-
bers of DCs have become accessible for large-scale
study and applications.
DCs are a central player in all immune responses,
both innate and adaptive. DCs are exceptionally po-
tent immunogens under inflammatory conditions, yet
are also critical to the induction and maintenance of
self-tolerance in the steady state. The heterogeneity of
DCs and their activation states afford investigators
more opportunities to define and manipulate the im-
mune response using these specialized leukocytes.
Human DCs are all bone marrow–derived leuko-
cytes and compose at least 4 types defined under
cytokine-driven conditions in vitro (Figure 1). In
addition, trace populations of DCs also circulate in
human blood. One type shares phenotypic (lineage
negative, CD11c?, CD86?, CD123?/low, and HLA-
DRbright) features with cytokine-generated myeloid
or conventional DCs in vitro. The other circulating
DCs, termed plasmacytoid because of their mor-
phological resemblance to plasma cells , are also
lineage-negative, CD86?, BDCA-2?, and HLA-
DRbright, but CD11cnegand CD123bright. Freshly iso-
lated plasmacytoid DCs express much lower levels of
major histocompatibility complex (MHC) and co-
Biology of Blood and Marrow Transplantation 13:23-32 (2007)
? 2007 American Society for Blood and Marrow Transplantation
stimulatory molecules than their conventional DC
counterparts . They also capture, process, and load
antigens onto MHC molecules less effectively. Thus,
these nonactivated plasmacytoid DCs are poor stim-
ulators of T lymphocytes. Interleukin (IL)-3, in com-
bination with CD40L or microbial products, leads to
full plasmacytoid DC activation, abundant secretion
of type I interferons (IFN), and more potent lympho-
cyte stimulation [4-6]. CD83 is the cardinal hallmark
of both plasmacytoid and conventional or myeloid DC
maturation in both mice and humans .
A potential point of confusion is that all murine
DCs, be they myeloid or plasmacytoid, express
CD11c, with the exception that CD11cneg/lowLang-
erhans cells (LCs) up-regulate CD11c only with mat-
uration. Along with low levels of CD11c, murine plas-
macytoid DCs also express B220 and Gr1 and
up-regulate CD123 only after Flt3-L treatment [8,9].
Monocyte-derived DCs (moDCs) and plasmacy-
toid DCs have been labeled DC1 and DC2, respec-
tively, because of their propensity to stimulate Th1
versus Th2 type responses, with plasmacytoid DCs
implicated as being somehow tolerogenic. This over-
simplification, however, neglects stimulation of more
varied T-cell responses, including the major physio-
logical role of plasmacytoid DCs as the most abundant
source of type I IFNs after activation by viruses [4-6].
It also overlooks the fact that both types of DCs can
stimulate the expansion of regulatory or suppressor T
cells [10-13], with immature or semimature forms
functioning in the steady state to maintain peripheral
tolerance and mature forms probably using this mech-
anism to turn off otherwise unchecked immune re-
sponses. Designations like DC1 and DC2 are best
avoided in favor of using the more specific terms for
DC Maturation and Migration to Secondary
Manipulation of immunity using DCs generated
in vitro should exploit the less mature and nonacti-
vated forms to promote tolerance and the activated
and mature forms to break tolerance and promote
immunity. That said, under physiologic steady-state
conditions, DCs are a major component of lymphoid
tissues. In this setting, DCs are mostly immature or
semimature and efficiently process self-antigens to
induce and maintain tolerance [14-16]. All DCs re-
quire some form of terminal maturation to become
fully immunogenic, however. Thus, DC maturation is
a pivotal event in the control of innate and adaptive
immunity. Microbial products constitute a physiologic
activation stimulus via Toll-like receptors (TLRs) on
both plasmacytoid and conventional DCs. CD40L
(CD154), either expressed by activated T cells or as a
multimeric recombinant protein, can also mature
DCs. A combination of inflammatory cytokines that
includes IL-1-?, tumor necrosis factor (TNF)-?,
IL-6, and prostaglandin E2  is often used to ma-
Figure 1. Development of human DC subsets. Precursors in blood and bone marrow (left section) can give rise to 4 types of DCs. Counterparts
exist in vivo for each DC type generated with cytokines in vitro, although the moDC has proven more elusive to identify in situ. Trace
populations of circulating myeloid or conventional DCs and plasmacytoid DCs also exist in blood. Terminal maturation and activation are
complex processes but are necessary for DCs to exert optimal immunogenicity. FL, Flt-3 ligand; GM, granulocyte macrophage colony-
stimulating factor; KL, c-kit-ligand. (Reprinted from The Journal of Immunology 2005;175:1373-1381 and used with permission, Copyright
2005 The American Association of Immunologists, Inc.)
J. W. Young et al.
64. Papadopoulos EB, Carabasi MH, Castro-Malaspina H, et al.
T-cell–depleted allogeneic bone marrow transplantation as
postremission therapy for acute myelogenous leukemia: free-
dom from relapse in the absence of graft-versus-host disease.
65. Mackinnon S, Papadopoulos EB, Carabasi MH, et al. Adoptive
immunotherapy evaluating escalating doses of donor leukocytes
for relapse of chronic myeloid leukemia after bone marrow
transplantation: separation of graft-versus-leukemia responses
from graft-versus-host disease. Blood. 1995;86:1261-1268.
66. Zhang Y, Joe G, Zhu J, et al. Dendritic cell–activated
CD44hiCD8?T cells are defective in mediating acute graft-
versus-host disease but retain graft-versus-leukemia activity.
67. Durakovic N, Bezak KB, Skarica M, et al. Host-derived Lang-
erhans cells persist after MHC-matched allografting indepen-
dent of donor T cells and critically influence the alloresponses
mediated by donor lymphocyte infusions. J Immunol. 2006;177:
68. Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with
B-cell lymphoma using autologous antigen-pulsed dendritic
cells. Nat Med. 1996;2:52-58.
69. Timmerman JM, Czerwinski DK, Davis TA, et al. Idiotype-
pulsed dendritic cell vaccination for B-cell lymphoma: clinical
and immune responses in 35 patients. Blood. 2002;99:1517-
70. Dzionek A, Fuchs A, Schmidt P, et al. BDCA-2, BDCA-3, and
BDCA-4: three markers for distinct subsets of dendritic cells in
human peripheral blood. J Immunol. 2000;165:6037-6046.
71. Lopez JA, Bioley G, Turtle CJ, et al. Single step enrichment of
blood dendritic cells by positive immunoselection. J Immunol
72. Berard F, Blanco P, Davoust J, et al. Cross-priming of naive
CD8 T cells against melanoma antigens using dendritic cells
loaded with killed allogeneic melanoma cells. J Exp Med. 2000;
73. Palucka AK, Ueno H, Connolly J, et al. Dendritic cells loaded
with killed allogeneic melanoma cells can induce objective clin-
ical responses and MART-1–specific CD8?T-cell immunity.
J Immunother. 2006;29:545-557.
74. Yuan J, Latouche JB, Hodges J, et al. Langerhans-type den-
dritic cells genetically modified to express full-length antigen
optimally stimulate CTLs in a CD4-dependent manner. J Im-
75. Gilboa E, Vieweg J. Cancer immunotherapy with mRNA-
transfected dendritic cells. Immunol Rev. 2004;199:251-263.
76. Paczesny S, Banchereau J, Wittkowski KM, et al. Expansion of
melanoma-specific cytolytic CD8?T cell precursors in patients
with metastatic melanoma vaccinated with CD34?progenitor–
derived dendritic cells. J Exp Med. 2004;199:1503-1511.
77. Fay JW, Palucka AK, Paczesny S, et al. Long-term outcomes in
patients with metastatic melanoma vaccinated with melanoma
peptide-pulsed CD34(?) progenitor–derived dendritic cells.
Cancer Immunol Immunother. 2006;55:1209-1218.
78. Thurner B, Haendle I, Roder C, et al. Vaccination with mage-
3A1 peptide-pulsed mature, monocyte-derived dendritic cells
expands specific cytotoxic T cells and induces regression of
some metastases in advanced stage IV melanoma. J Exp Med.
79. Mannering SI, McKenzie JL, Fearnley DB, et al. HLA-DR1-
restricted bcr-abl (b3a2)-specific CD4?T lymphocytes respond
to dendritic cells pulsed with b3a2 peptide and antigen-present-
ing cells exposed to b3a2-containing cell lysates. Blood. 1997;
J. W. Young et al.