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Nanoparticles coated with fragments of the body's own proteins are shown to induce T cells of the immune system to adopt regulatory functions that suppress autoimmune reactions involving these self-antigens. See Article p.434
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DAVID WRAITH
A
utoimmune diseases arise when our
immune system attacks our own
tissues. The immune cells of affected
individuals are insufficiently tolerant towards
certain ‘self’ proteins and attack them as if
they were foreign. Helper Tcells (THcells)
play a central part in autoimmune diseases
because they orchestrate the function of other
cells in the immune system, including Bcells,
cytotoxic Tcells and macrophages. Current
treatments for autoimmune diseases tend to
suppress the whole immune system or, at best,
inhibit the movement or function of Tcells;
such approaches inevitably increase the risk
of infection and cancer. The ideal treatment
for autoimmune diseases would convert the
function of THcells from disease-causing
to disease-regulating without affecting the
rest of the immune system. In this issue,
Clemente-Casares etal.
1
(page 434) describe
coated nano particles that mediate this con-
version by binding to receptors on potentially
self-reactive Tcells.
The authors’ approach can be considered
as a type of antigen-specific immunotherapy.
Antigens are the molecular structures that
induce the activation of T or Bcells; for Tcells
these are generally small fragments of proteins
(peptides). Each Tcell can express a different
surface receptor, thereby allowing our immune
system to respond to countless different anti-
gens, including self-antigens. Antigen-specific
immunotherapy is designed to dampen the
immune response to a particular antigen or
set of closely associated antigens. This con-
cept has been used to treat allergies for more
than a century
2
, but specific immunotherapy
for autoimmune diseases lagged behind until
the discovery that T
H
cells are activated by pep-
tides bound to MHC classII proteins. This led
to the design of peptides that selectively target
T
H
cells without risking the activation of self-
reactive cytotoxic Tcells or Bcells3.
How can exposure to a peptide known to
stimulate self-reactive T
H
cells switch off the
disease they cause? This is best explained by
the ‘two-signal’ rule of T-cell activation4,5.
All antigens, whether self or foreign, must be
broken down into peptides, which must then
bind MHC classII proteins and be displayed at
the surface of antigen-presenting cells (APCs)
to activate THcells. This is referred to as
signal1. The APC must also upregulate co-
stimulatory molecules, such as CD80 and
CD86, to provide the second signal required
for TH-cell survival and proliferation.
What happens when THcells receive signal1,
but not signal2? Historically, this was thought
to induce a state of unresponsiveness known
as anergy6. Now, Clemente-Casares etal.
show that treating T
H
cells with nano particles
coated with a peptide bound to MHCclassII
proteins (pMHC-NP treatment) triggers
signal1 alone. But rather than simply inducing
anergy, the treatment drives the THcells to
differentiate into cells that have characteris-
tics of regulatory Tcells; these act to dampen
immune responses.
The resulting regulatory cells exert their
function by secreting the anti-inflammatory
proteins IL-10 and TGF-β. Furthermore, the
cells express the transcription factor T-bet and
make the cytokine signalling molecule IFN-γ
during their differentiation. These character-
istics imply that they derive from cells of the
TH1 subset of THcells (Fig.1). The differen-
tiation of IL-10-secreting Tcells— referred
to here as TR1-like cells — from TH1 cells is
an immunoregulatory mechanism known
to prevent excessive immune responses to a
range of infections7–9. These cells mediate a
negative feedback mechanism involving sup
-
pression of co-stimulatory molecules on APCs
and a reduction in the inflammatory proteins
secreted by APCs10.
What are the downstream effects of the
AUTOIMMUNITY
Antigen-specific immunotherapy
Nanoparticles coated with fragments of the body’s own proteins are shown to induce T cells of the immune system to adopt
regulatory functions that suppress autoimmune reactions involving these self-antigens. S A .434
T
H
1 cell
Nanoparticle
MHC class II
Peptide
T
R
1-like cell
CD8
+
T cell
B cell
Regulatory B cell
IL-10
IL-10
IL-10
Antigen-presenting cell
Inhibition by
T
R
1-like cell
CD4
+
T cell
Figure 1 | Coated nanoparticles induce differentiation of regulatory Tcells. Clemente-Casares etal.1
produced nanoparticles coated with peptide fragments of the body’s own proteins that are associated
with autoimmune disease, bound to MHC classII proteins. They show that treating mice with these
nanoparticles modifies the function of TH1 cells that have receptors specific for that particular peptide:
instead of inducing an immune response against the self-protein, the TH1 cells differentiate into regulatory
(TR1-like) Tcells that secrete the anti-inflammatory protein IL-10. The IL-10 promotes the differentiation
of Bcells into IL-10-secreting regulatory Bcells, and also modifies the ability of antigen-presenting cells
(APCs) to present the specific peptide to immune cells. Furthermore, the TR1-like cells can inhibit the
activation of helper (CD4+) and cytotoxic (CD8+) Tcells that are specific for other peptides presented by the
same APC, and thus mediate bystander suppression. In this way, TR1-like cells can target APCs in tissues
affected by autoimmune reactions and thereby suppress the inflammation associated with the disease.
422 | NATURE | VOL 530 | 25 FEBRUARY 2016
NEWS & VIEWS For News & Views online, go to
nature.com/newsandviews
© 2016 Macmillan Publishers Limited. All rights reserved
ANNA M. KIETRYS & ERIC T. KOOL
T
he fact that chemical modifications to
DNA bases can alter gene expression
without changing the nucleic-acid
sequence has been known for more than a
decade. But the key regulatory function of
many such epigenetic modifications to mes-
senger RNA molecules has been recognized
only recently1–3. A simple mark — the methyl
group — is widely observed in DNA and its
associated histone proteins, and has been
studied in mRNA in the forms of 5-methyl-
cytosine and N6-methyladenosine. On
page441 of this issue, Dominissini etal.4
present a new member of the mRNA methyl-
marked family, N1-methyl adenosine, and
propose that its presence in mRNAs has an
influence on biological processes. What is
surprising about this modification is that it has
previously been described as a form of cellular
damage5.
N1-methyladenosine (m1A) is unusual in
having a positive charge at physiological pH
(other bases are uncharged) and a methyl
group that blocks the Watson–Crick base-
pairing edge of adenine. The modification
was previously documented in transfer RNA
molecules, where it plays a crucial part in
the formation of tertiary RNA structure.
The methyl group forces the m1A base to
pair with a non-Watson–Crick configura-
tion6, and the positive charge has also been
hypothesized to exert an electrostatic influ-
ence on protein interactions7. Dominissini
etal. propose that this base modification may
have similar biophysical effects in mRNAs: it
could affect base-pairing inter actions close
to the site at which protein translation starts,
and might alter RNA folding and electrostatic
interactions.
m1A was previously known to be formed
by the exposure of RNA molecules to alkylat-
ing agents, and under alkaline conditions it
is converted to N6-methyladenosine (m6A)
through the Dimroth rearrangement8 (Fig.1).
This is potentially a big problem in analysis,
TR1-like cells induced by pMHC-NP treat-
ment? Clemente-Casares etal. show that
the cells suppress the function of APCs and
reinforce immune regulation by promot-
ing IL-10 production by Bcells (Fig.1). The
authors verify the specificity of their approach
by using different experimental models of
autoimmune disease. pMHC-NPs carrying
peptides from collagen, an antigen derived
from joints, suppressed disease in a mouse
model of rheumatoid arthritis, but not in mice
with experimental autoimmune encephalitis
(EAE), a model of multiple sclerosis. Con-
versely, pMHC-NPs carrying peptides of
antigens from the central nervous system con-
trolled EAE but not collagen-induced arthri-
tis. This confirms that the immune regulation
induced by pMHC-NP treatment is specific to
the antigen and tissue, and so to the disease.
Furthermore, the pMHC-NPs did not need
to target Tcells specific for all peptides in the
affected organ. Even peptides from sub-domi-
nant antigens (weaker antigens that do not trig-
ger disease in the first place) were able to induce
TR1-like cells that suppressed helper and cyto-
toxic Tcells with activity against other antigens
(Fig.1). Thus, although this treatment is highly
antigen-specific at the induction phase, it can
influence other arms of the immune response
locally, through induction of regulatory B-cell
activity and suppression of helper and cyto-
toxic Tcells specific for different antigens.
This requires that the peptide fragment from
the inducing antigen and the other antigens are
presented by the same APC.
Is it possible that such bystander suppression
could lead to systemic immune suppres -
sion by switching off cells not involved in the
autoimmune response, thereby increasing
the risk of infection or cancer? No: bystander
suppression will be limited to lymph nodes
associated with the affected organ and will
influence only those APCs presenting the
relevant self-antigen. Such specificity is clearly
demonstrated by Clemente-Casares and col-
leagues— mice treated with pMHC-NPs are
protected against the relevant autoimmune
disease, yet show undiminished responses to
infections and foreign antigens.
The experimental treatments in this study
use well-character-
ized models of auto-
immune disease.
But is this work just
another therapeu-
tic approach that
works in mice but
will never work in
humans? It seems
not: the authors
show that pMHC-
NP treatment leads
to differentiation
and proliferation of human TR1-like cells in
immunodeficient mice transplanted with
human T and Bcells, demonstrating that
pMHC-NP treatment works on human cells.
The teams work also suggests that treatment
with pMHC-NPs is more effective than with
monomers of MHC-bound peptides at an
equivalent dose. Furthermore, pMHC-NP
treatment seems to be more suppressive than
the application of peptide alone; however, the
doses and routes of administration in these tests
were not comparable.
There is overwhelming evidence that
peptide antigens can induce TR1-like cells11
and suppress autoimmune diseases in both
mice and humans
9
. The fact that pMHC-NP
treatment induces TR1-like cells similar to
those seen after the administration of peptide
alone suggests that pMHC-NPs mimic the
APC to which therapeutic peptides bind
invivo. The challenge with each of these
approaches will be to find the optimal dose and
route of administration for treating people. As
these options progress towards clinical trials, it
is vital that their mechanism of action is inves-
tigated in detail so that patients can benefit
fully from antigen-specific immunotherapy for
auto immune disease.
David Wraith is at the School of Cellular and
Molecular Medicine, University of Bristol,
BristolBS8 1TD, UK.
e-mail: d.c.wraith@bristol.ac.uk
1. Clemente-Casares, X. et al. Nature 530, 434–440
(2016).
2. Noon, L. Lancet i, 1572–1573 (1911).
3. Larché, M. & Wraith, D. C. Nature Med. 11, S69–S76
(2005).
4. Lafferty, K. J. & Cunningham, A. J. Aust. J. Exp. Biol.
Med. Sci. 53, 27–42 (1975).
5. Baxter, A. G. & Hodgkin, P. D. Nature Rev. Immunol.
2, 439–446 (2002).
6. Schwartz, R. H. Annu. Rev. Immunol. 21, 305–334
(2003).
7. O’Garra, A., Vieira, P. L., Vieira, P. & Goldfeld, A. E.
J.Clin. Invest. 114, 1372–1378 (2004).
8. Trinchieri, G. J. Exp. Med. 204, 239–243 (2007).
9. Sabatos-Peyton, C. A., Verhagen, J. & Wraith, D. C.
Curr. Opin. Immunol. 22, 609–615 (2010).
10. Gabryšová, L. et al. J. Exp. Med. 206, 1755–1767
(2009).
11. Burton, B. R. et al. Nature Commun. 5, 4741
(2014).
The author declares competing financial interests.
See go.nature.com/ukjrkv for details.
This article was published online on 17 February 2016.
EPIGENETICS
A new methyl mark
on messengers
The presence of an N1 methyl group on adenine bases in DNA and RNA was
thought to be a form of damage. Results now show that it also occurs at specific
sites in messenger RNAs, where it affects protein expression. S A .441
“The treatment
drives the TH cell
to differentiate
into cells with
characteristics of
regulatory T cells;
these act to
dampen immune
responses.”
25 FEBRUARY 2016 | VOL 530 | NATURE | 423
NEWS & VIEWS RESEARCH
© 2016 Macmillan Publishers Limited. All rights reserved
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Interleukin (IL)-10 is a cytokine that modulates both innate and adaptive immunity, primarily by exerting antiinflammatory effects. IL-10 was originally thought to be produced only by T helper (Th)2 cells, but is now known to be made by a variety of cell types. During many infections, CD4(+) T cells produce both interferon (IFN)-gamma, the signature Th1 cytokine, and IL-10. New data now show that the IL-10 produced by effector Th1 cells helps limit the collateral damage caused by exaggerated inflammation. But this control may also limit the effectiveness of the immune response, resulting in a failure to fully eliminate pathogens.
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Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4(+) T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4(+) T cells. Analysis of the CD4(+) T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4(+) T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy.
Allogeneic reactions have conventionally been considered as typical immune responses by one population of cells to antigens present on the other. This view is inadequate, since it does not explain many features of these reactions, among which are: (1) reactivity is much higher between different strains within a species than between species, in spite of the much greater antigenic disparity in the second case; (2) a very high proportion of cells may respond to allogeneic stimuli; (3) major histocompatibility differences are not essential for vigorous allogeneic reactions; (4) the responding population need not be immunologically competent to respond to antigens of the stimulating population; (5) the stimulating population must be both metabolically active and immunocompetent.
Article
T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4(+) and CD8(+) cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naïve T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely.
Article
Effective immune responses against pathogens are sometimes accompanied by strong inflammatory reactions. To minimize damage to self, the activation of the immune system also triggers anti-inflammatory circuits. Both inflammatory and anti-inflammatory reactions are normal components of the same immune response, which coordinately fight infections while preventing immune pathology. IL-10 is an important suppressive cytokine, produced by a large number of immune cells in addition to the antigen-driven IL-10-producing regulatory and the naturally occurring suppressor CD4+ T cells, which is a key player in anti-inflammatory immune responses. However, additional mechanisms have evolved to ensure that pathogen eradication is achieved with minimum damage to the host. Here we discuss those mechanisms that operate to regulate effector immune responses.