The n e w e ng l a n d j o u r na l of m e dic i n e
Review Article
From the Sean N. Parker Autoimmune
Research Laboratory (J.A.B.) and the Dia-
betes Center (J.A.B., M.A.), University of
California, San Francisco, San Francisco.
Address reprint requests to Dr. Bluestone
at the UCSF Diabetes Center, 513 Parnas-
sus Ave., Box 0540, San Francisco, CA
94143, or at ­jeff​.­bluestone@​­ucsf​.­edu.
N Engl J Med 2020;383:1156-66.
DOI: 10.1056/NEJMra1911109
Copyright © 2020 Massachusetts Medical Society.
1156
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Dan L. Longo, M.D., Editor
Tolerance in the Age of Immunotherapy
Jeffrey A. Bluestone, Ph.D., and Mark Anderson, M.D., Ph.D.​​
T
he induction and maintenance of robust immune tolerance
has been the holy grail of immunology for decades. In the absence of robust
unresponsiveness of the immune system to self antigens (immune toler-
ance), uncontrolled reactivity can lead to disorders like food allergies and autoim-
mune diseases. Although the first seminal experiments in tolerance were con-
ducted in the 1950s,1 the development of novel tolerance-inducing therapeutic
drugs has been fraught with clinical challenges and few durable successes, in spite
of advances in our understanding of the fundamental aspects of the immune sys-
tem. However, in recent years, new breakthroughs in our understanding of these
basic mechanisms and maintenance of immune tolerance have led to clinical suc-
cesses in the fields of organ transplantation and allergic and autoimmune dis-
eases. Moreover, novel peptide therapeutic drugs, anti–T-cell antibodies, and cell
therapies have set the stage for short-term treatments of autoimmune diseases that
have long-term efficacy and eliminate the need for continuous therapy.
During the past few decades, a more detailed understanding of the molecular
events associated with T-cell recognition and activation has advanced various ap-
proaches to tolerance, such as reprogramming, costimulatory blockade, check-
point inhibition, and antigen-specific immune regulation. The term “unresponsive-
ness” that has been associated with immune tolerance refers to a lack of
pathogenic immunity characterized by immune-cell inactivation or deletion or to
the diversion of pathogenic immunity to protective immunity through the engage-
ment of regulatory cells, deviation in cell differentiation, or development of im-
mune barriers. Thus, implicit in current approaches to the development of tolero-
genic drugs is the assumption that successful therapies would treat and prevent
allergic and autoimmune diseases, as well as lead to immunosuppression-free
organ and stem cell–derived tissue transplantation and protein-replacement ap-
proaches in congenital diseases such as hemophilia. Many of the most recent
therapeutic successes involve novel drugs that have been designed to break toler-
ance to cancers that are dependent on tumor-specific and microenvironment-
mediated tolerogenic signals. However, these treatments can lead to autoimmune
syndromes, underscoring the delicate balance between breaking tolerance to treat
tumors and altering immune homeostasis systemically.
Mech a nisms of Im mune T ol er a nce
The Thymus and Central Tolerance
In the early 1960s, Jacques Miller and Max Cooper independently defined two
distinct types of immune cells, T and B cells, that are the hallmark of the antigen-
specific adaptive immune system.2,3 T cells orchestrate immune responses both
indirectly, by providing soluble and membrane-associated signals that promote the
survival, expansion, and differentiation of B cells (which produce antibodies that
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The New England Journal of Medicine
 Toler ance in the Age of Immunother apy

Glossary

Autoimmune regulator (AIRE): A protein that binds to chromatin and regulates the process of gene transcription such
that a plethora of self-proteins are ectopically expressed in medullary thymic epithelial cells (mTECs) involved in
thymic selection.
Bystander suppression: Immunosuppression in a local environment through direct cell-to-cell contacts or short-range
cytokines that are independent of specific antigen reactivity.
Infectious tolerance: Tolerance that results when forkhead box P3 (FOXP3)–positive regulatory T cells (Tregs) convert
conventional T cells into peripherally derived Tregs through secretion of the suppressive cytokines transforming
growth factor β (TGF-β), interleukin-10, or interleukin-35 or indirectly through the alteration of antigen-presenting
cells.
In vitro–induced Tregs (iTregs): Tregs that can clearly be distinguished from Treg populations generated in vivo; iTregs
can be induced by cytokines such as TGF-β, altered antigen-presenting cells, or costimulatory blockade.
Medullary thymic epithelial cells (mTECs): An epithelial-cell population present in the thymic medulla that expresses
AIRE protein and is responsible for negative selection and Treg development.
Peripherally derived Tregs (pTregs): Tregs that develop in tissue sites from conventional CD4+ T cells as a consequence
of exposure to certain cytokines, microbial products, or altered antigen-presenting cells.
T-cell receptor (TCR) repertoire: The diverse use of unique TCR alpha and beta chains to recognize individual antigen–
major histocompatibility complexes.
Thymus-derived Tregs (tTregs): Tregs induced as a consequence of negative selection, in which high-affinity, self-reac-
tive T cells develop into FOXP3-positive Tregs.
Toll-like receptors (TLRs): A class of proteins, usually expressed on macrophages and dendritic cells, that recognize
structurally conserved molecules derived from microbes to activate the innate immune system.

support productive humoral immunity), and di-
rectly, by killing foreign and infected tissues
through cellular and soluble mediators.3 T cells
recognize foreign antigens through a unique,
highly diverse set of T-cell receptors (TCRs) de-
signed to mediate immunity without the collat-
eral damage of destroying native tissues. In a
parallel system, regulatory T cells (Tregs) recog-
nize self-peptides and, when activated, control
self-reactive pathogenic T cells. This complex,
dynamic process of self–nonself discrimination
is the basis of immune tolerance. In this review,
we focus on TCR αβ cells in immune tolerance,
given their dual role in pathogenicity and im-
mune suppression, and on the wealth of new
approaches being developed to induce or break
tolerance by targeting TCR αβ cells and the anti-
gen-presenting cells that drive their function.
The thymus is the birthplace of T cells. Bone
marrow–derived CD34+ stem cells migrate to the
thymus, where they differentiate and acquire the
expression of the TCR. Each T cell expresses its
own unique receptor, which is composed of a
heterodimer of two chains (TCRα and TCRβ),
each of which is generated through somatic re-
combination of multiple genetic elements, includ-
ing the addition of a few nucleotides at the site
of recombination. This combinatorial diversity
results in a broad TCR repertoire with more than
1010 distinct receptor combinations and is key to
the ability of the T-cell population as a whole to
recognize the vast array of potential targets (see
the Glossary). However, in each person, this
repertoire is restricted and skewed as each T cell
is selected for its ability to bind a self-peptide in
the context of a polymorphic and polygenic com-
ponent of its ligand, molecules encoded by the
major histocompatibility complex (MHC). This
selection step, termed positive selection, ensures
that T cells are able to recognize a foreign pep-
tide antigen bound to proteins encoded by spe-
cific self MHC alleles, most commonly MHC
class I and class II molecules for CD8+ and
CD4+ T cells, respectively.4 (Details are provided
in note 1 in the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org.)
After positive selection, T cells pass through
an important second selection step, called nega-
tive selection. This is a filtering step to remove
T cells that have a strong binding affinity to
self-peptides that are bound to the same MHC
molecules and are consequently autoreactive. Such
T cells arise by chance through the stochastic
gene-rearrangement process that generated the
TCR and, thus, could potentially lead to autoim-
munity. To accomplish negative selection, a small,
resident cell subset, termed medullary thymic epi-
thelial cells (mTECs), and bone marrow–derived

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

Antigen- Antigen-
presenting cell presenting cell

CD86 CD80 CD80 CD86

MHC MHC
Inhibitory
Peptide Peptide
Signal 1 Signal 2 signal
TCR TCR
CD28 CTLA-4

T cell CTLA-4 T cell CD28

Inactivation
Activation Inhibition of proliferation and cytokine
Proliferation production by T cells
Cytokine production T-cell exhaustion and apoptosis
Prevention of anergy Altered antigen-presenting-cell function
Differentiation of helper T cells and suppressive cytokine production

Figure 1. Two-Signal Models of Costimulatory and Inhibitory Pathways.

Initiation of a productive T-cell response involves integration of a primary signal delivered through the T-cell recep-
tor (TCR) and major histocompatibility complex (MHC)–peptide, followed by a second signal delivered through the
CD28–CD80 or CD28–CD86 pathway (Panel A). After initiation of T-cell activation, other inhibitory checkpoint inter-
actions can shut down T-cell activity (Panel B). Pathways that may be affected as a consequence of both positive and
negative second signals are listed at the bottom of the figure. CTLA-4 denotes cytotoxic T-lymphocyte–associated
protein 4.

dendritic cells5 interact with the maturing T cells. Peripheral Tolerance

The mTECs express a transcriptional activator
called the autoimmune regulator (AIRE), which
enables the expression of thousands of other-
wise tissue-restricted proteins, so that peptides,
derived from these proteins, are displayed to
developing T cells; this process results in robust
elimination of self-reactive CD4+ and CD8+ con-
ventional T cells.6 The key role of AIRE-positive
mTECs in central tolerance is indicated by the
clinical manifestation of a profound, multiorgan
autoimmune syndrome, called autoimmune poly-
glandular syndrome type 1 (APS1), in patients
with mutations in AIRE.7
As efficient as the thymus is in eliminating self-
reactive cells, many self-reactive T cells escape
thymic negative selection, which leads to the
need for peripheral mechanisms to ensure that
self-tolerance is maintained.8 A variety of cell
types and processes control peripheral tolerance,
including cells of the adaptive and innate im-
mune system and signaling components within
T cells and antigen-presenting cells themselves.9
Effective T-cell signaling requires both engage-
ment of the primary antigen-specific receptor and
a second, costimulatory signal to induce prolif-
eration, differentiation, and survival.10 A consti-

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 Toler ance in the Age of Immunother apy

tutive T-cell–surface molecule, CD28, was the

first T-cell costimulatory receptor to be identi- CD28 CD80
fied (Fig. 1).11 The ligands CD80 and CD86 are +
expressed selectively on antigen-presenting cells, CD86
CTLA-4
especially after activation through innate ago- –
nists of toll-like receptors (TLRs) and soluble
PD-1 PDL1 or L2
factors. Only cells that recognize nominal anti- –
gen — often termed “signal one” to reflect the TIM-3
first signal delivered to T cells during an activa- –
tion event — respond to a second costimulatory BTLA HVEM
–
signal essential for complete T-cell activation. Antigen-
T cell presenting cell
Blockade of costimulatory pathways leads to an TCR–CD3 MHC-pep
antigen-specific apoptotic cell death, clonal in- +
activation, and tolerance induction.12 Studies in
CD70 CD27
animal models have shown that costimulatory +
blockade with monoclonal antibodies and soluble CD154 CD40
+ +
forms of the CD80 and CD86 high-affinity re-
ceptor, cytotoxic T-lymphocyte–associated pro- + OX40L OX40
tein 4 (CTLA-4), induces tolerance in the context ICOS B7RP-1
of autoimmune disorders or organ transplanta- +
tion.12 Identification of additional costimulatory CD137L CD137
+
pathways, such as CD154–CD40, CD11A–CD54,
CD18–CD54, and CD2–CD58, has validated and
extended the two-signal model of T-cell activa- Cytokines
(TGFβ, interleukin-1, interleukin-6, interleukin-10, interleukin-12, interleukin-18)
tion. These findings have provided new thera-
peutic opportunities for blocking autoreactive
T-cell activity and inducing long-term tolerance Figure 2. Additional Costimulatory and Checkpoint Pathways.
without the need for continuous therapy.13 In addition to the two-signal models of costimulatory and checkpoint path-
Additional controls on the surface of activated ways, additional stimulatory and inhibitory pathways (indicated by plus and
T cells — so-called negative regulators, or check- minus signs, respectively) influence the immune response, including mole-
cules of the tumor necrosis factor (TNF)–related family, other members of
points — are as important as costimulatory
the CD28 family, adhesion molecules, and T-cell immunoglobulin and mu-
pathways in controlling T-cell activation. How- cin (TIM) molecules. The various stimulatory and inhibitory pathways can
ever, unlike costimulatory pathways, checkpoints, influence and be influenced by cytokines. Pep denotes peptide, and TGF-β
including CTLA-4 and programmed death 1 transforming growth factor β.
(PD-1),14 shut down immune activation when
engaged by their ligands, which leads to active
tolerance induction (Fig. 1). Direct evidence of a ance is the presence of specialized cell popula-
role for checkpoints in tolerance has been shown tions designed to suppress pathogenic immune
in cases in which checkpoint pathways have responses that inadvertently target self-tissue.
been inhibited. For instance, gene ablation or These include naturally occurring Treg cells and
treatment with checkpoint inhibitors can exacer- in vitro–induced Treg (iTreg) cells, as well as
bate autoimmunity and, in some cases, break interleukin-10–producing type 1 regulatory T (Tr1)
tolerance induced by other therapies.15 Thus, cells and transforming growth factor β (TGF-β)–
targeting of checkpoint pathways has resulted in producing type 3 helper T (Th3) cells.16 Of these
a new generation of tolerance-manipulating drugs subsets, the most extensively studied are Tregs,
(Fig. 2). Inhibition of checkpoint pathways has a subset of the self-reactive CD4+ T cells that
revolutionized cancer immunotherapy by turn- develop as a consequence of the expression of a
ing once deadly cancers such as melanoma and master transcriptional repressor, forkhead box
non–small-cell lung cancer into treatable dis- P3 (FOXP3). FOXP3 alters the differentiation of
eases.14 Checkpoint agonists are being used in the mature CD4+ T-cell population into this
the treatment of autoimmune disease and organ- regulatory T-cell subset, which plays a funda-
transplant rejection, as described below. mental role in immune homeostasis.17 Func-
Another key mechanism of peripheral toler- tional disruption of FOXP3, either genetically (in

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 The n e w e ng l a n d j o u r na l
Scurfy mice and patients with the IPEX [immune
dysregulation, polyendocrinopathy, enteropathy,
X-linked] syndrome) or pharmacologically, leads
to severe autoimmune disorders that cause death
at a very young age unless the patient is given a
bone marrow transplant.18
The primary source of Tregs is the thymus,
where the cells are generated by an alternative
developmental pathway. During negative selec-
tion, a subset of developing T cells expressing
TCRs with high affinity develop into Treg pre-
cursors that up-regulate FOXP3, leading to a
stable epigenetic state and resulting in a mature,
self-reactive population of thymus-derived Tregs
(tTregs) that populate lymphoid and nonlym-
phoid tissues in the periphery.19,20 The role of
Tregs in the periphery is to halt self-reactivity
and promote tissue repair and regeneration
(Fig. 3).21,22 AIRE-expressing mTECs play a role
in the generation of tTregs through presentation
of tissue-specific antigens. Moreover, AIRE is
expressed in a subset of bone marrow–derived
cells in peripheral lymphoid organs and, thus,
may influence tolerance in peripheral tissues.23
This finding highlights the connection between
peripheral tolerance and T-cell development in
the thymus.
Tregs are generated in the immune periphery
as well, under conditions in which naive CD4+
T cells encounter antigen in the context of sup-
pressive factors such as TGF-β, interleukin-10,
bacterially derived metabolic products, or altered
stimulatory pathways. Under certain conditions,
antigen presentation leads to the induction of
stable FOXP3 and transformation of conven-
tional T cells into peripherally derived Tregs
(pTregs).24 Thus, unlike tTregs, which develop in
the thymus from T cells undergoing negative
selection based on high self-reactivity, pTregs
develop from a conventional peripheral T-cell
repertoire selected for low self-reactivity. A grow-
ing number of examples show that Tregs recog-
nize commensal bacteria, which have many
characteristics normally attributed to self-anti-
gens. This process diversifies the Treg repertoire,
which may be most effective in shutting down
inflammatory responses. Moreover, pTregs may
recognize modified proteins, such as citrulli-
nated peptides, hybrid peptides, and phosphory-
lated proteins, which are often present in auto-
immune states but not in the thymus. Together,
the combination of tTregs and pTregs, as well as
interluekin-10–producing Tr1 cells and TGF-β–
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of m e dic i n e
producing Th3 cells, may provide the broadest
antigen-recognition repertoire for controlling
pathogenic self-reactivity. Moreover, because of
thymic involution in adulthood, the development
and maintenance of tolerance may differ accord-
ing to age, with peripheral pathways having a
more important regulatory role in autoimmunity
in adults than in children25 (note 2 in the Supple-
mentary Appendix).
Antigen-presenting cells, including tolerogenic
dendritic cells, immature macrophages, suppres-
sor antigen-presenting cells of the myeloid lin-
eage, and even certain B-cell subsets, function
in conjunction with Tregs and other suppressor
T cells to control immunity. These cells develop
in response to a variety of cell-surface and sol-
uble factors, including those controlled by
Tregs.26-28 For instance, Tregs express high levels
of the checkpoint CTLA-4, which can block
CD28-mediated costimulation and deliver in-
hibitory signals that change antigen-presenting
cells into tolerogenic cells.29,30 Tregs, as well as
other regulatory cells, produce cytokines, such
as interleukin-10, interleukin-35, TGF-β, and
other soluble factors involved in metabolism,
such as indoleamine 2,3-dioxygenase. The Tregs
can induce myeloid-derived suppressor cells and
alter antigen presentation.27,31 Tregs express CD39
and CD73, which affect the duration, magni-
tude, and chemical nature of purinergic signals
delivered to immune cells through the conver-
sion of ADP or ATP to adenosine.32 Finally,
metabolic products of the gut microbiome, in-
cluding the production of short-chain fatty acids
such as butyrate, can have a profound effect on
immune function. These and other regulatory
factors can act on antigen-presenting cells to
promote the generation of Tr1 cells and Tregs or
directly affect pathogenic T cells, altering dif-
ferentiation, trafficking, and function. Oral tol-
erance studies with short-chain fatty acids sup-
port a strong interface between the immune
system and resident microbiota33 (Fig. 4).
Thus, it is clear that a dynamic, homeostatic
immune system has evolved to deal with endog-
enous and exogenous insults. There is a balanc-
ing act between the need to develop potent effec-
tor cells in order to combat foreign pathogens
and the need for homeostatic control of the
immune system to shut down unwanted autoin-
flammation, as has been reported in some pa-
tients with coronavirus disease 2019 (Covid-19)34
and autoimmunity.
 Toler ance in the Age of Immunother apy

A Pathways in Thymus

AIRE-expressing
mTEC T cell

T cell
FOXP3
tTreg

T cell Naive
T cells

Apoptosis of
T cells

B Pathways in Immune Periphery

Naive
CD4+ T cell
CD4+
effector T cell AIRE-expressing
eTAC

Antigen-
presenting cell
CD4+
Antigen- effector T cell
Conventional macrophages presenting cell
and dendritic cells
CD8+
effector T cell

Tolerogenic macrophages
and dendritic cells

CD8+
effector T cell
Apoptosis
of effector FOXP3
T cells pTreg

Pathogenic Protective

Figure 3. Tolerance-Inducing Pathways in the Thymus and Periphery.

The majority of cells interacting with autoimmune regulator (AIRE)–expressing medullary thymic epithelial cells (mTECs) during thymic
development undergo negative selection and die (Panel A). A subset of high-affinity, self-reactive CD4+ T cells interact with the mTECs,
leading to the development of regulatory T cells (Tregs). The remaining mature naive T cells migrate into the immune periphery, where
they have either a pathogenic role in mediating immunity (Panel B, left) or a protective role as peripherally derived Tregs (through inter-
action with tolerogenic antigen-presenting cells and cytokines) that control potential autoreactive responses (Panel B, right). Additional
cell types, such as extrathymic AIRE–expressing cells (eTACs), can also modify potentially autoreactive T cells.

Inducing T ol er a nce tion has been the use of broadly immunosup-

pressive drugs, which carry substantial risks of
Historically, the only option for patients with serious side effects. Approved therapies, such as
autoimmune diseases or organ-transplant rejec- calcineurin inhibitors, glucocorticoids, and tumor

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 The n e w e ng l a n d j o u r na l
Microbiome
CD4+
Suppressive factors effector T cell
SCFAs
Antigen-
Interleukin-2
presenting cell Bystander
suppression
Treg
Th3
Tr1
CD4+ Treg
Infectious
effector T cell tolerance Th3
Tr1
Figure 4. Activation and Functional Consequences of Suppressive Cells.
Tregs and other suppressive cells circulate and reside in lymphoid and so-
matic tissues to control unwanted autoimmune and inflammatory respons-
es. Multiple cell–cell contacts, as well as soluble molecules (including the
production of metabolites by microbiota), are generated by Tregs or anti-
gen-presenting cells after Treg interactions to control immunity. Tregs can
also act through bystander suppression, leading to dominant local immu-
nosuppression and tolerance induction. IDO denotes indoleamine 2,3-di-
oxygenase, SCFA short-chain fatty acid, Th3 type 3 helper T cell, and Tr1
type 1 regulatory T cell.
necrosis factor α and interleukin-1 antagonists,
require continuous treatment and target the end
stage of the immune dysfunction rather than the
induction of tolerance. An improved understand-
ing of the molecular and functional basis for
immune tolerance has driven the development
of tolerogenic drugs that may fundamentally
change the therapeutic landscape.
Resetting the Immune System
The most effective way to generate immune tol-
erance would be to reset and rebalance the im-
mune system in order to prevent the develop-
ment and progression of the autoimmune
response. In this regard, two approaches — autol-
ogous hematopoietic stem-cell transplantation
(HST) and massive immune-cell depletion —
have been pioneered. Both of these methods are
intended to induce tolerance through exposure
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of m e dic i n e
to the tolerogenic antigen during regeneration
and recovery of the immune system. Autologous
HST has been reported to halt the progression
of certain forms of autoimmunity, such as multi-
ple sclerosis.35 Combining autologous and donor-
derived HST can result in lasting tolerance to the
donor MHC while allowing effective immune
reconstitution (i.e., mixed chimerism).36,37 The
immune-cell depletion approach to rebooting
the immune system has been enabled by the use
of broad immune-depleting agents such as alem-
tuzumab (anti-CD52 antibody), B-cell–depleting
agents (rituximab, ocrelizumab, and obinutuzu-
mab), and antilymphocyte antibody therapies.38-41
These drugs have been successful in slowing the
progression of disease, in some cases through
the elimination of antigen presentation by the
autoreactive B cells, which are very efficient in
capturing and presenting autoantigens.38,42 How-
ever, both autologous HST and the broad cell-
depleting strategies lead to the elimination of
immune-cell subsets, including those involved in
protection from infection and, potentially, cancer.
Targeting Pathogenic T Cells
In the past several years, treatments have been
developed to selectively target the highly acti-
vated, pathogenic T cells involved in mediating
tissue-reactive immunity. These treatments in-
clude an anti-CD3 monoclonal antibody (teplizu-
mab), a soluble form of the CD2 costimulatory
receptor LFA-3 (alefacept), and low-dose antithy-
mocyte globulin.40,43,44 These biologics have been
shown to induce apoptosis and functional inac-
tivation of highly activated effector cells, leaving
naive T cells and Tregs intact or even expanding
the regulatory pathways. This class of therapeu-
tic drugs has been shown to be efficacious in a
variety of autoimmune diseases, even when pa-
tients were treated for only a short period of
time. In the case of teplizumab, Herold and col-
leagues reported that the median time until dis-
ease onset was prolonged by more than 3 years
and the median disease-free survival was 5 or
more years among patients who were at risk for
type 1 diabetes and who were treated for only
2 weeks.45,46 The therapy not only delays the de-
velopment of disease but also may induce more
sustained tolerance in some patients. In trials
conducted by the Immune Tolerance Network,
one or two courses of teplizumab given over a
3-month period to patients with newly diagnosed
nejm.org September 17, 2020
 Toler ance in the Age of Immunother apy
type 1 diabetes led to prolonged preservation of
c-peptide (insulin) production, with no increase
in rates of infection or cancer. A significant per-
centage of residual CD8+ effector T cells ex-
pressed an exhausted or anergic T-cell pheno-
type that has been shown to be the major
marker of tumor tolerance.47 These results high-
light the importance of targeting pathogenic
T cells to induce tolerance while maintaining
naive T cells and regulatory pathways to preserve
immune competence and homeostasis. Moreover,
a combination of these therapies, as well as the
pro-Treg drugs described below, provides an op-
portunity to rebalance the immune system, since
it is likely that control of autoimmunity requires
both a decreased number of pathogenic T cells
and increased regulatory activity.
The second approach to tolerance induction
with more selective tolerogenic therapeutic drugs
has been the development of inhibitors of the
costimulatory pathway, as noted above and
shown in Figures 1 and 2. Two soluble CD28
antagonists, abatacept and belatacept (CTLA-4–
IgG1 and mutant CTLA-4–IgG1, respectively),
have been approved by the Food and Drug Ad-
ministration for the treatment of rheumatoid
arthritis and kidney-transplant rejection, respec-
tively.48,49 Unfortunately, the ability of these
drugs to induce protracted tolerance in humans
is unclear. In a clinical trial involving patients
with newly diagnosed type 1 diabetes, treatment
with abatacept for 6 months resulted in signifi-
cant prolongation of insulin production, as com-
pared with insulin production in the control
group, but this protection diminished over time.50
One reason for the decline in the efficacy of the
drug may have been its depletion of Tregs,
which may be essential for the development of
tolerance.12,51 Treg development and survival are
dependent on CD28 signaling in vivo.52 A sec-
ond generation of costimulatory antagonists
(including those that block CD154–CD40 inter-
actions) that may synergize with CD28 costim-
ulatory blockade are currently being evaluated
in a number of clinical settings.53 The substan-
tial effect of antibodies directed at negative
regulators in cancer immune therapy, including
multiple antibodies against PD-1 and its ligand,
PD-L1, and antibodies against CTLA-4 to pro-
mote activation signals to T-cells, opens up a
new area for tolerance induction.54 New treat-
ments are being developed to activate (rather
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than block) the key checkpoints and inactivate
pathogenic T cells.
The third approach, the induction of antigen-
specific tolerance with the use of autoantigen
therapeutic drugs, has been the most challeng-
ing.55-58 These therapies are potentially the most
selective in eliminating autoreactive pathogenic
T cells while reducing the risks of infections and
cancer, which make broadly immunosuppressive
agents problematic. However, the requirement for
knowledge of the autoantigen, the large number
of pathogenic epitopes, and the consequence of
epitope spreading (which expands the number of
pathogenic epitopes) complicate these deletional
therapies. Such therapies have nevertheless been
successful in the treatment of immune respons-
es to allergens, such as peanuts, dust mites, and
certain grasses, and metabolic deficiencies, such
as hemophilia,59,60 in which the uncontrolled
inflammatory responses to the proteins after
exposure can prevent the use of these lifesaving
treatments. In a seminal proof-of-principle study,
newborn children at high risk for atopic aller-
gies were randomly assigned to be exposed to
peanuts or to have no exposure over a 5-year
period. A majority of the children who were ex-
posed to peanuts had a higher sustained reduc-
tion in the incidence of peanut allergy than
those who had not been exposed.61 At a mecha-
nistic level, tolerance was due in part to immune
deviation from a pathogenic IgE response to a
nonpathogenic IgG response.
In an equally dramatic demonstration of the
power of antigens to induce tolerance under the
right conditions, allograft tolerance has been
maintained after withdrawal of immunosuppres-
sive drugs in a subset of liver-transplant recipi-
ents, presumably because of the constant expo-
sure of alloantigen in a protolerogenic hepatic
environment.62 These successes have expanded
to the use of peptides, either administered alone
intravenously or coupled to cells, nanoparticles,
or other multimeric scaffolds; DNA vaccines,
which incorporate both antigenic peptides and
tolerogenic therapeutics to modify TCR recogni-
tion; immobilized HLA–peptide complexes; and
tolerogenic dendritic cells pulsed with multiple
peptides.63 Peptide-induced tolerance has often
been associated with the induction of Tregs or
tolerogenic dendritic cells. Uptake of antigen
through scavenger receptors, such as DEC-205,
SR-A, or MARCO, may alter the cell phenotype
1163
 The n e w e ng l a n d j o u r na l
and function and, in some cases, down-regulate
costimulatory ligands. Thus, peptide therapies tap
into some of the most basic aspects of T-cell
activation. The safety of antigen-specific thera-
peutic approaches has been shown in multiple
phase 1 clinical trials using several autoantigenic
peptides from multiple proteins, and controlled
phase 2 trials of efficacy are now under way.64,65
Targeting Regulatory Pathways
Defects in or defective regulation of key immune
cells such as tolerogenic FOXP3-positive Treg cells
has been documented in several types of human
autoimmunity, which suggests that enhanced
Treg numbers, increased Treg functioning, or
both might stop autoimmunity. Several approach-
es have been undertaken to increase or enhance
Treg numbers and activity in patients with auto-
immune disorders. These approaches include
treatment with low-dose interleukin-2 and inter-
leukin-2 mutants to selectively increase Treg
numbers and functioning, short-term combina-
tion therapies that promote the development of
regulatory cells, such as rapamycin (sirolimus),
and the coadministration of tolerogenic peptides,
as described above.66-69 One of the more active
research areas has been the administration of ex
vivo–generated, tolerogenic cellular therapies,
which can result in a shutdown of autoimmu-
nity, potentially lasting for years.15,70 Treg ther-
apy takes advantage of two distinct factors that
enhance tolerance: bystander suppression and
infectious tolerance. These mechanisms enable
Tregs to suppress the immune response widely
within a local environment and create a tolero-
genic environment in which other local cells
take on a tolerogenic phenotype, which leads to
broadening of the number and specificities of
the cells involved in the control of unwanted im-
munity. More than 50 active and completed
clinical trials are testing the safety and efficacy
of Treg cell therapy for indications such as kid-
ney or liver transplantation, pemphigus vulgaris,
systemic lupus erythematosus, inflammatory
bowel disease, autoimmune hepatitis, allergy,
and asthma. In patients with chronic graft-versus-
host disease, Treg-cell therapy alleviated symp-
toms, and pharmacologic immunosuppression
could be reduced.71 In addition to Tregs, a sec-
ond suppressive T-cell population, Tr1 cells, is
being used therapeutically to induce tolerance.72
Efforts are under way to increase the potency
1164 n engl j med 383;12  nejm.org  September 17, 2020
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
and life span of these regulatory cells by insert-
ing specific TCRs or chimeric antigen receptors
and using gene editing to modify durability and
stability, alter trafficking, and enhance tissue
repair of the adoptively transferred cells.
Additional potentially tolerogenic approaches
using antigen-presenting cells are also being
tested in the clinic, including the use of mesen-
chymal stromal cells73 and dendritic cells.74,75
Each approach has advantages and disadvantages
with respect to the potential for “off-the-shelf”
treatments, the ability to modify the cell therapy
with current genetic approaches, and the mecha-
nism (direct vs. bystander) of suppression. Clin-
ical-grade tolerogenic dendritic cells, generated
in vitro, are being tested in autoimmune and
organ-transplant settings to induce clonal dele-
tion of pathogenic T cells in vivo or to induce the
generation of antigen-specific regulatory T and
B cells.76-78 All these approaches are focused on the
induction of active, dominant, antigen-specific
tolerance and thus avoid the need to delete all
T cells against potential pathogenic specificities.
Finally, other cell therapies are being tested
to treat autoantibody-mediated autoimmunity, in-
cluding the use of genetically engineered effec-
tor T cells transduced with a chimeric antigen
receptor that is directed at the cell-surface CD19
molecule. On adoptive transfer, the T cells are
triggered by CD19 on B cells, which induces
cytolytic activity and B-cell destruction.79,80 An-
other approach is the expression of autoantigen
(target protein) chimerized to the signal domains
of a typical chimeric antigen receptor (a so-called
chimeric autoantigen receptor), which when put
into CD8+ T cells, leads to the destruction of
B cells and plasma cells expressing a receptor
that recognizes the autoantigen.79 These cells are
being introduced into clinical practice and will
soon be assessed for their safety and efficacy in
a variety of autoantibody-mediated diseases.
C onclusions
Despite the genetic predisposition observed in
the majority of autoimmune diseases, the inabil-
ity to predict the development of autoimmunity,
coupled with the likelihood that disease has al-
ready developed by the time patients come to
clinical attention, means that treatment is usu-
ally initiated after the onset of disease. Efforts
are under way to predict the onset of diseases
 Toler ance in the Age of Immunother apy

such as rheumatoid arthritis and type 1 diabetes. combination therapies will be required to estab-
Individual tolerogenic therapies may be more lish long-term tolerance.
effective if they can be used before sufficient Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
tissue has been damaged to develop a disease We thank Dr. Gerald Nepom at the Benaroya Institute for
phenotype.45 Achieving durable tolerance is like- kindly reading and advising on an earlier version of the manu-
ly to require eliminating or regulating disease script and the members of the Bluestone and Anderson labora-
tory for their work, which has resulted in many of the ideas
effectors and repairing damaged tissue. The com- highlighted in this review, and for their ongoing advice and
plexity of the process suggests that the use of commitment to the discovery effort.

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