Asia Pacific

Review Article Allergy

Immunological mechanisms of tolerance: Central,

peripheral and the role of T and B cells
Xun Meng1, Janice A. Layhadi1, Sean T. Keane1, Natanya J.K. Cartwright1, Stephen R. Durham1, and
Mohamed H. Shamji1,*

ABSTRACT
T and B cells are key components of the adaptive immune system. Through their immune properties and their interactions
with other immune cells and cytokines around them, they build a complex network to achieve immune tolerance and maintain
homeostasis of the body. This is achieved through mechanisms of central and peripheral tolerance, both of which are associated
with advantages and disadvantages. For this reason, the immune system is tightly regulated and their dysregulation can result
in the subsequent initiation of various diseases. In this review, we will summarize the roles played by T cells and B cells within
immune tolerance with specific examples in the context of different diseases that include allergic disease. In addition, we will also
provide an overview on their suitability as biomarkers of allergen-specific immunotherapy.
Keywords: Center tolerance; B cell; peripheral tolerance; T cell

1. Introduction Central tolerance is a process in which autoreactive lymphocytes

are selectively prevented from entering the periphery and occurs
Immune tolerance is crucial for the maintenance of homeo-
in either the bone marrow or the thymus. B cells mature and
stasis and health. When immune tolerance is dysfunctional
undergo central tolerance via receptor editing in the bone mar-
and unable to maintain a balanced homeostatic environ-
row, while central tolerization of T cells occurs in the thymus via
ment, disease can occur. Immune tolerance is defined differ-
negative selection. In either case, autoreactive cells are efficiently
ently depending on the disease type. For example, in the case
eliminated during this process. Despite the rigor of central toler-
of transplantation, tolerance is defined as graft acceptance
ance, the system is imperfect, and therefore autoreactive T and
without the need for continued immunosuppressive therapy.
B cells may still escape into the periphery. Unwanted peripheral
Whereas in allergy, tolerance manifests as prolonged unre-
immune activation is inhibited by peripheral tolerance mecha-
sponsiveness to allergen challenge and exposure after desen-
nisms, including deletion and anergy [1]. If peripheral tolerogenic
sitization therapy. In the context of autoimmune disease,
balance is lost, various diseases can occur. Therefore, many stud-
tolerance is achieved when long-term improvement of disease
ies have focused on understanding the balance between effector
symptoms has been achieved, accompanied by a decrease in
and regulatory compartments in health and disease in hopes of
the need for disease-modifying therapy. In other diseases such
manipulating the underlying mechanisms for therapeutic benefit.
as cancer, tolerance typically refers to the ability of tumor cells
This review will discuss T cell and B cell tolerance separately,
to evade the body’s immune system, resulting in uncontrolled
focusing on recent advances and research findings in the mainte-
cell proliferation and metastasis.
nance of tolerance and homeostatic balance.
Immune tolerance represents the long-term or permanent con-
straint of potentially harmful immune responses towards innocu-
ous stimuli. This regulation is achieved through both central and
peripheral immune mechanisms targeting T and B lymphocytes. 2. T cell tolerance
Central tolerance of T cells occurs in the thymus, where hemato-
poietic lymphoid progenitors migrate to develop into CD4+CD8+
1
Department of National Heart and Lung Institute, Imperial College London, double-positive (DP) thymocytes expressing the T cell antigen
London, United Kingdom receptor (TCR). DP cells undergo positive and negative selec-
*Correspondence to Mohamed H. Shamji Immunomodulation and Tolerance tion in the cortex and medulla of the thymus respectively, based
Group, Allergy & Clinical Immunology, Inflammation, Repair and Development, on the affinity of their TCR for self-peptide-associated major
National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College histocompatibility complex class I (MHC-I) or MHC class II
London, South Kensington Campus, London SW7 2AZ, United Kingdom
(MHC-II) molecules. In the cortex, all DP thymocytes capable
Tel: +44-020-7594-3476
of binding pMHC molecules presented by cortical thymic epi-
Email: [Link]@[Link] thelial cells are positively selected for and continue into the thy-
Copyright © 2023. Asia Pacific Association of Allergy, Asthma and Clinical mic medulla. Those that fail to interact with pMHC molecules
Immunology. This is an open-access article distributed under the terms of the
undergo apoptosis [2]. In the medulla, the level of TCR affinity
Creative Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the work provided for pMHC molecules presented on the surface of thymic den-
it is properly cited. The work cannot be changed in any way or used commercially dritic cells (DCs) and medullary thymic epithelial cells deter-
without permission from the journal. mines their fate [3]. T cells carrying TCRs with high affinity
Received: 2 November 2023; Accepted: 14 November 2023 are deleted, those with intermediate affinity are diverted into
Published online 11 December 2023 regulatory T cells (Tregs), and those with low affinity become
[Link] conventional T cells and exit to the periphery (Fig. 1). However,

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Figure 1. The mechanism of T cell tolerance. Central tolerance of T cells occurs in the thymus. Hematopoietic lymphoid progenitors migrate to cortex, where
they are screened by thymic epithelia cells and develop into CD4+CD8+ double-positive (DP) thymocytes expressing the T-cell antigen receptor (TCR). DP cells
migrate to the medulla. After screening for the ability to bind to self-peptide-associated major histocompatibility complex class I (MHC-I) or MHC class II (MHC-II)
molecules on the antigen-presenting cell (APC) surface, DP cells develop into CD4+CD8+ DP thymocytes expressing the TCR. Screening for binding capacity of
molecules culminating in Treg CD8+ T cells, and CD4+ T cells migrate to lymph node undergo peripheral tolerance. Peripheral tolerance mechanisms, such as
exhaustion, deletion, anergy, and regulation are mainly relied upon to suppress the activity of self-reactive T cells. Exhaustion and deletion are realized through
inhibiting cell function or proliferative capacity of effector T cell and apoptosis. Anergy describes a state of hyporesponsiveness of naive T cells to TCR stimuli
after exposure to antigen. Treg cells regulate by inhibiting effector T cell activity and B cell proliferation via interleukin-(IL)-10, Transforming growth factor-β (TGF-
beta), and IL-35.

central tolerance is not infallible, and some self-reactive T cells in early infection, in fact some T cells seen in early infection
may still escape to the periphery. Peripheral tolerance mecha- already display some of the characteristics associated with
nisms, such as Treg regulation and the exhaustion, anergy, or exhausted T cells such as a monofunctional cytokine signa-
deletion of self-reactive T cells, are mainly relied upon to sup- ture [7]. It is therefore possible that T cells with ‘exhausted’
press the activity of self-reactive T cells (Fig. 1). phenotypes are generated in parallel with Tconv cells in early
infection, but their population dominance occurs later in infec-
tion, during the chronic phase. In cases of T cell exhaustion in
3. Exhaustion cancer, this non-functional phenotype can be reversed through
Although not typically associated with tolerance, T cell exhaus- use of checkpoint blockade of PD-1/PD-L1, indicating the cells’
tion represents an important mechanism of tolerance in specific functional capacity is not itself diminished. The exhausted
immunological situations. Phenotypically, exhausted T Cells phenotype may therefore describe cells experiencing increased
(Tex) have evidence of reduced functional and proliferative resistance to activation rather than being intrinsically incapable
capacities and display elevated levels of inhibitory receptor of such.
expression, including that of Programmed cell death protein-1 Although counterintuitive at first, this less aggressive,
(PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA- exhausted T cell state has been proposed to protect the host
4), Lymphocyte-activation gene 3 (LAG3), Cluster of differen- whilst still managing the disease to optimise disease outcome.
tiation 244 (CD244), Cluster of differentiation 160 (CD160), In other words, it is a form of tolerance designed to protect the
T Cell immunoreceptor with Ig and ITIM domains (TIGIT), host [8]. In a murine study by Cornberg et al [9], they describe
Cluster of differentiation 38 (CD38), Cluster of differentiation how mice infected with lymphocytic choriomeningitis virus
39 (CD39), and T cell immunoglobulin (Ig) domain and mucin (LCMV) at high concentrations experienced T cell exhaustion
domain-containing protein 3 (TIM3) [4]. These exhausted T and very little immunopathology, however mice given an inter-
cells are classically associated with chronic viral infection and mediate dose of virus experienced only partial T cell exhaustion
cancer; both instances in which T cells experience prolonged but suffered significant immunopathology in the liver and lungs,
antigen stimulation. In fact, T-cell failure or “exhaustion” was leading to severe disease and death. This outcome strongly
first described in chronic viral infections in mice [5]. However, supports the idea that exhaustion is a protective mechanism
in recent times it has been argued that Tex cells’ reduced func- designed to protect the host during periods of prolonged acti-
tional capacity may not be an unavoidable consequence of vation. The benefits of this are clear in terms of autoimmunity
prolonged antigen stimulation, but a designated differentiation to self-antigen, graft vs. host disease [10] and in response to
program [6]. There has yet to be definitive evidence that Tex chronic viral infections. Through prevention of ongoing inflam-
cells in chronic infection derive from those active T cells seen mation, tissue damage, and chronic auto-reactivity which are
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damaging to the host, Tex cells may be seen as essential for long- they are involved in the induction or maintenance of anergy
term host survival. function, and whether they can be used exclusively as markers
Although T cell exhaustion can increase the severity of of anergic CD4+ T cells in humans, is currently subject to fur-
chronic disease by leading to tumour growth and persistent ther study [16].
viral infections, there is also evidence of their ability to continue Although stimulation of the TCR is the main driving force
to enact disease control. For example, one hallmark feature of behind the hyporesponsiveness and resulting dysfunction of
multiple chronic infections is mutated T cell epitopes, the pres- both Tex and anergic T cells, these states are unique. The main
ence of which evidences T-cell driven selective pressure, despite difference between anergy and exhaustion is that the signals
their ‘exhausted’ state in cases of established chronic infection. that induce these 2 cell types are different. Anergic T cells are a
In addition, it has been shown that removal of CD8 T cells in product of co-stimulation-deficient T-cell activation, while Tex
Macaques infected with chronic SIV results in rapid increases cells are T cells which have experienced prolonged TCR and
in viral titre [11], supporting the idea that T cells still main- costimulatory molecule stimulation [17].
tain some functionality and in this case display continued anti-­ Anergy helps to prevent the immune system from attacking
viral activity despite prolonged antigen stimulation. Overall, healthy tissues [18]. However, T cell unresponsiveness has also
although T cell exhaustion is not typically considered a periph- been implicated in disease, such as cancer or chronic infection,
eral tolerance mechanism, it has been shown to be essential for where T cells become unresponsive and fail to generate an effec-
long-term host survival and is in essence an immune mecha- tive immune response. Again highlighting the careful balancing
nism which prevents immune cell activity that is damaging to act that is immune tolerance, and its potential to be exploited in
the host, which is the core of what immunological tolerance is. novel theraputic therapies [19].

4. Anergy 5. Deletion
T cell anergy describes a state of hyporesponsiveness of naive T T cell deletion is a tolerance mechanism most associated with
cells to TCR stimuli after exposure to antigen. Anergy is estab- central tolerance; however, there is evidence that this also
lished by the activation of intracellular pathways triggered by occurs in the periphery. Evidence for this form of tolerance
the interaction of the TCR with pMHC in the absence of costim- was shown by Chen et al [18]. They demonstrated that oral
ulation [12]. When T cells encounter antigens, they require 2 administration of antigen led to apoptotic deletion of antigen-­
signals to be fully activated. The first signal is the binding of specific T cells peripherally in the Peyer’s patches of mice [20].
the TCR to the antigen presented on the antigen-presenting cell Following this initial discovery, the cellular mechanism of this
(APC), and the second signal is the binding of costimulatory form of peripheral tolerance was investigated by Davey et al
molecules on the APC. In the absence of costimulation, T cells [19]. Using a transgenic OVA-expressing murine model, it was
become unresponsive. shown that tolerance against OVA-specific CD8+ T cells was
This differs from quiescence and ignorance. Quiescence is maintained by cross-presentation of OVA by DCs and sub-
independent of antigen-TCR interaction and refers to a state sequent deletion of OVA-specific T cells. Investigation of the
in which T cells are at rest or inactive but still alive and meta- molecular mechanism found that this deletion failed upon over-
bolically active. Ignorance occurs when T cells are not able to expression of BCL-2, indicating BCL-2 suppression is essen-
recognize a particular antigen, either because the antigen is not tial for this form of peripheral tolerance [21]. The location
properly presented to them or because the T cells lack the spe- of peripheral deletion investigated by Carlow et al [20]. They
cific receptor required to recognize the antigen. found that when female mice, that were made to express T cells
T cell anergy is considered a peripheral tolerance mecha- specific for a male antigen, were injected with male lymphoid
nism. T cell anergy can be broadly categorized as either clonal cells, apoptotic phenotypes of their male antigen-specific CD8+
anergy or adaptive tolerance. Clonal anergy is a state in which T cells were quickly observed in secondary lymphoid organs.
T cells do not proliferate but still produce a limited amount This suggested that secondary lymphoid organs are the site of
of effector cytokines. Its function is maintained without con- peripheral T cell deletion [22, 23]. Collectively, there is mount-
tinuous antigen exposure, and this form of T cell anergy can ing evidence that cell deletion is a peripheral tolerance mech-
be reversed by interleukin (IL)-2 [13]. Conversely, adaptive anism for T cells. However, these studies have been conducted
tolerance maintains anergy in response to prolonged antigen in mice and therefore may not perfectly describe the tolerance
stimulation, inhibiting both cell proliferation and cytokine mechanisms in humans. This form of peripheral tolerance is
production. Strong TCR signaling may induce anergy or dele- important for termination of immune responses. Towards the
tion in CD8+ T cells, which generally express both inhibitory ends of an immune reaction, T cells begin expressing death
receptors CTLA-4 and C-C chemokine receptor type 7 (CCR7). ligands such as Fas which facilitate their deletion and terminate
It has not been fully determined whether differences in TCR the immune response. The importance of this has been demon-
signaling affect the induction of CD4+ T cell anergy. However, strated in mice. It has been shown that mice lacking Fas ligand
it has been suggested that low-affinity TCR interaction with experience extensive self-reactivity and autoimmune reactions
pMHC can induce anergy, resulting in CD4+ T cells that lack [24]. Similarly, in the human disease, ALPS in which there are
the capacity to proliferate or produce IL-2 [14]. Alteration mutations in Fas or FasL leading to autoimmune reactions and
of the timing of the TCR-pMHC interaction can also lead to lymphadenopathy [25].
CD4+ T cell anergy, for example, a short-duration TCR-pMHC
interaction or low TCR signaling [14, 15]. Overall, the identifi-
cation of anergic CD4+ T cells in humans has been challenging, 6. Regulation: Tregs
especially considering the lack of distinct markers. Evidence Regulation is an important mechanism of T cell tolerance, medi-
currently exists in murine models in which a high expression ated mainly by Tregs. In the periphery, Tregs with a self-skewed
of CD73 and FR4 has been observed in anergic cells. Whether TCR repertoire are very sensitive to self-antigens and microbial

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antigens; much lower concentrations (from 10 to 100 fold) of 7. Inhibitory molecules

peptide/MHC will activate Tregs [22]. Tregs suppress the activ-
7.1. Interleukin-10
ity of both autoreactive T cells that escaped central deletion and
T cells that cross-react with self-antigen as a result of molecu- IL-10 is an important anti-inflammatory cytokine that regulates
lar similarity with microbial antigens [23]. In the early 2000s, immune responses and maintains immune homeostasis. It is pro-
human CD25+CD4+ Tregs were discovered and were thought duced by various cells of the immune system, including T cells, B
to have the same phenotype and function as mouse Tregs, play- cells, macrophages, and DCs. IL-10 contributes to the suppres-
ing an important role in antitumor, antimicrobial, and graft sion of immune responses that may lead to inflammation and
immunity. Following the discovery of CD25+CD4+ natural Tregs tissue damage. For example, it inhibits Tconv cell proliferation
(nTregs), it was discovered that these cells specifically expressed and activation, accelerates depletion, suppresses the antigen-­
transcription factor Foxp3, and that deletion or mutation of presenting function of APC cells, and also induces iTreg cells,
FoxP3 led to the absence or hypofunctioning of nTregs. Loss of which in turn can produce high levels of IL-10 to help maintain
nTreg function results in a range of systemic immune diseases their suppressive function and promote immune tolerance [32].
or infections, such as type I diabetes, allergies, and inflamma- IL-10 can activate the STAT3 signaling pathway to promote
tory bowel disease [26]. There are more than 70 Foxp3 mutant Treg development and expansion [33] and can inhibit the pro-
genes reported so far, 40% of which can cause severe autoim- duction of pro-inflammatory cytokines such as IL-6 and IL-12
mune disease [27], and the rest can also cause varying degrees of by DCs, which in turn promotes Treg expansion and suppres-
symptoms. Immune dysregulation polyendocrinopathy enterop- sive functions [34, 35]. IL-10 also enhances Treg expansion and
athy, X-linked (IPEX) syndrome is one example of a disorder suppressive functions by upregulating CTLA-4 and PD-1 [36].
that is characterized by dysfunction of Tregs, which can result in IL-10 also plays a role in regulating the differentiation of naive
immune dysregulation. The first report of Treg transplantation T cells into Teff cells. In the absence of IL-10 signaling, naive
for the treatment of immunodeficiency diseases was carried out T cells are more likely to differentiate into pro-inflammatory
in FoxP3 mutant mice, which provided the basis for the subse- Type-1 T helper cells (Th1) or Type-17 T helper cells (Th17)
quent treatment of human IPEX disease and other autoimmune cells, thereby promoting self-immune responses. However, IL-10
diseases [26]. signaling can redirect the differentiation of naïve T cells to a
Tregs can be divided into various subsets based on their regulatory phenotype, leading to the development of Treg and
developmental pathway; thymus-derived Tregs (tTregs), the promotion of immune tolerance [37]. Overall, IL-10 plays
peripherally-derived pTregs, and in vitro-induced Tregs (iTregs). a key role in maintaining T cell tolerance by regulating Treg
tTregs, differentiate from CD4+ thymocytes [27]. They mainly function and promoting the differentiation of naïve T cells into
recognize self-antigens and constitute a significant proportion regulatory phenotypes.
of FoxP3+ Tregs within the periphery. While some CD4+CD25- In cancer and autoimmune disease, IL-10 can act as both
conventional T cells (Tconvs) can express Foxp3 stably, they positive and negative regulator of the immune response. As a
eventually become peripherally-derived Tregs (pTregs). Tconvs negative regulator of the antitumor immune response, IL-10
that are stimulated under special conditions in vitro, can dif- can inhibit the activation and function of immune cells (includ-
ferentiate into iTregs with the expression of Foxp3. The spe- ing T cells and natural killer cells) involved in the antitumor
cific TCR of pTreg can recognize infectious antigens and immune response. On the other hand, it has been shown that
harmless microbial antigens, an important process for mucosal IL-10 enhances CD8+ T cell-mediated antitumor immunity by
tolerance. In mice, this distinction between pTregs and tTregs regulating DCs [38]. Similarly, in autoimmune diseases, the
can be made using the surface marker Neuropilin 1 (NRP1), presence of increased expression of IL-10 [39] can help suppress
which is found exclusively on pTregs [28]. However, there inflammatory responses and limit tissue damage, while they
is no way to distinguish pTregs from tTregs in humans yet. also play a role in mediating pro-inflammatory effects in certain
Despite the lack of distinction, in general, Tregs are defined autoimmune diseases, such as multiple sclerosis and rheumatoid
as Foxp3+CD25+CD127low/−. The immunosuppressive func- arthritis [40, 41].
tion of Tregs in vivo or in vitro relies on multiple mechanisms. In inflammatory diseases, the effect of IL-10 is more favor-
CD39 and CD73, which are highly expressed on the surface able, wherein it plays a role in inhibiting the production of
of Tregs, catabolize ATP into adenosine. Adenosine is then able pro-inflammatory cytokines, such as TNF-α and IL-6. In aller-
to bind the adenosine A2a Receptor (ADORA2A). Binding of gic inflammatory reactions, IL-10 inhibits the production of
ADORA2A on Teff cells can promote their differentiation into pro-inflammatory cytokines and chemokines associated with
Tregs, skewing immune activity towards tolerance. In addition, allergic reactions. It also promotes the differentiation and func-
adenosine can also promote tolerogenic APC activity, reduc- tion of Treg cells, contributing to the suppression of allergic
ing their ability to present antigen to and activate Teff cells. responses and maintenance of immune tolerance. Studies have
Adenosine thus both directly and indirectly inhibits Teff cell shown that IL-10 levels are reduced in allergic individuals, sug-
activity [29]. Contact between FoxP3+ Treg-expressing CTLA-4 gesting that IL-10 deficiency may contribute to the development
and DCs induces DCs to express indoleamine-2, 3-dioxygenase and severity of allergic reactions [42].
(IDO), which activates the kynurenine metabolic pathway. In Overall, IL-10 has a complex and multifaceted role in regu-
this pathway, tryptophan is metabolised into kynurenine. This lating immune responses in autoimmune diseases, and further
significantly affects Teff cells which are highly dependent on studies are needed to fully understand its function and potential
tryptophan for many of their effector functions [30]. In addi- therapeutic applications.
tion to the above mechanisms, immunosuppression by Tregs can
also be achieved by humoral factors such as anti-inflammatory
7.2. Transforming growth factor-β
cytokines (IL-2, IL-10, Transforming growth factor-β [TGF-β],
and IL-35) or secreted/intracellular molecules (granzyme, cyclic TGF-β is a multifunctional cytokine that plays a key role in
AMP, and IDO) [31]. the regulation of immune responses, including T cell tolerance.

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It is produced by a variety of immune cells, such as Tregs, DCs, activity of autoreactive T cells, prevent them from attacking
and macrophages. It acts on T cells and APCs to inhibit their auto-antigens and transplanted tissues, and promote the activity
activation and differentiation and plays a crucial role in the of Treg cells, thereby suppressing the activity of pro-inflammatory
induction and maintenance of T cell tolerance. Similar to IL-10, immune cells, promoting the production of anti-inflammatory
TGF-β has a role in regulating the differentiation of naive T cells cytokines, and ultimately enhancing immune tolerance. IL-35
toward a regulatory phenotype during their development, leading expression has been found to be upregulated in patients with
to the development of Treg cells and the promotion of immune autoimmune diseases such as rheumatoid arthritis, multiple scle-
tolerance; conversely, in the absence of TGF-β signaling, naive rosis, and systemic lupus erythematosus (SLE) [52, 53]. Shamji
T cells are more likely to differentiate into pro-inflammatory et al [54] reported that IL-35 and IL-35-induced Tregs (iTR35)
Th1 or Th17 cells, thus promoting autoimmune responses [43]. cells are potential novel immune regulators induced by grass pol-
TGF-β also promotes the differentiation of Th17 cells to Tregs len sublingual immunotherapy (SLIT). Moreover, Zeng et al [55]
[44]. In addition, TGF-β inhibits the function and survival of show that IL-35 inhibits apoptosis, adhesion, migration, and
APCs [43, 45]. TGF-β also promotes the differentiation of Th17 activation of eosinophils in AR patients.
cells to Tregs [44]. In addition, TGF-β inhibits the function and The role of IL-35 in tumors is more complex, and its action
survival of APCs [45], subsequently preventing the activation of may depend on the type of tumor and the tumor microenviron-
self-reactive T cells and promoting their deletion or anergy in ment. Many studies have shown that IL-35 can induce an immu-
the thymus and peripheral tissues [45]. nosuppressive environment by interacting with other immune
The role of TGF-β in disease development and immunother- cells, such as Treg, Th17, or tumor-infiltrating lymphocytes
apy is complex. Depending on the stage of the disease and the [56]. At the same time, they are known to promote tumors by
microenvironmental context, it can both promote and suppress secreting cytokines such as IL-6 and G-CSF [57], and inhibiting
the immune response. In cancer immunotherapy, for example, anti-inflammatory cytokine IFN-γ [58].
TGF-β can have both tumor-promoting and tumor-suppressive
effects. In the early stages of cancer, TGF-β promotes the activa-
tion and proliferation of effector T cells and natural killer cells 8. B cell tolerance
to enhance the immune response against cancer cells, thereby B cells are classically renowned for their capacity to differentiate
attacking and killing them. In the late stages of cancer, however, into antibody-secreting plasma cells, providing protection from
TGF-β can induce the differentiation of Tregs, thereby inhib- invading pathogens. B cells also have important antigen present-
iting the activation of effector T cells and promoting tumor ing capacity, an understudied field which is often overshadowed
growth and metastasis. Suppression of TGF-β signaling has by the other professional APCs such as DCs and monocytes.
been proposed as a potential strategy for cancer therapy [46]. An example of this is the dominant APC role B cells play in the
However, the potential side effects of TGF-β inhibition on nor- maintenance and differentiation of primed T cells into germi-
mal tissue homeostasis and wound healing should be carefully nal centre Tfh cells, providing co-stimulatory signals through
considered [47]. In allergic diseases such as asthma, TGF-β has CD80, CD86 and ICOSL [59].
been shown to promote disease progression by stimulating col- B cells have also demonstrated involvement in chronic inflam-
lagen production, inhibiting collagen breakdown, and activat- matory responses, for example in allergic and autoimmune dis-
ing fibroblast, which can induce airway remodeling [48, 49]. eases. However, B cells also have a regulatory capacity through
On the other hand, TGF-β has also been shown to enhance the secretion of immunosuppressive cytokines (Fig. 2). In this
immune tolerance and attenuate excessive immune responses section the central and peripheral tolerance relating to B cells
by promoting the differentiation of Tregs, thereby relieving will be discussed.
asthma [50]. In addition, TGF-β can promote the production of
anti-inflammatory cytokines (eg, IL-10), further reducing aller-
gic inflammation. 9. Central tolerance
In other diseases, such as autoimmune diseases or transplant In 1890, the concept of B cell tolerance was proposed by
rejection, TGF-β may be used to induce the differentiation of Ehrlich et al [60] when they studied the specificity of serum.
Treg cells or tolerogenic DCs, thereby suppressing autoimmu- B cell tolerance was understood to be an acquired property of
nity or preventing transplant rejection. However, TGF-β may the immune system that controls the specificity of antibodies
also suppress normal immune responses, leading to infections in a way that avoids autotoxicity. But this definition does not
and other complications resulting in graft failure. Overall, comprehensively explain the auto-specific reaction in healthy
TGF-β signaling can have both beneficial and detrimental individuals, which may be meaningful to health. The tolerogenic
effects on the immune response. A better understanding of the process that undifferentiated B cells undergo in the bone mar-
role of TGF-β in various diseases and the development of more row is known as central tolerance. Central tolerance is mainly
selective and targeted TGF-β modulators are needed to achieve achieved through the deletion, anergy, and B cell receptor (BCR)
optimal immunotherapy. editing of B cells. When a self-antigen bind to the BCR with
high affinity the B cell undergoes clonal deletion whereas when
the self-­antigen binds with lower affinity this can cause inac-
7.3. Interleukin-35 tivation of the B cell without deletion, also known as anergy
IL-35 is a member of the IL-12 family, a potent anti-inflammatory [61, 62]. Fulcher et al [63] and Cyster et al [64] extend the con-
cytokine, and a heterodimer consisting of Epstein-Barr cept of anergy by suggesting that peripheral anergic B cells are
virus-induced gene 3 (EBI3) and IL-12p35. It is produced excluded from lymphoid structures and are gradually deleted as
mainly by Treg, Breg [51], endothelial cells, smooth muscle cells, they compete with nonautoreactive cells.
and monocytes. During the development of BCR B cells, a considerable part of
IL-35 has a protective role in autoimmune diseases, transplant the B cells will edit the BCR receptor because of self-reactivity,
rejection, and allergic diseases. It has been shown to inhibit the though the exact proportion is currently unknown. Studies have

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Figure 2. The mechanism of B cell tolerance. The B cell precursor completes central tolerance in the bone marrow. Immature B cell receptor binds to
self-antigen and may cause high acitivity, resulting in clonal deletion or anergy, whereas immature B cells that only undergo moderate activity may move to the
lymph nodes to participate in peripheral tolerance. Self-antigen interacts with B cell receptor (BCR), and B cells with strong interaction will undergo apoptosis
and deletion, while B cells with weak interaction will develop into anergic B cells. Immature B cells without interaction, will develop into mature B cells. Breg
cells play an important role in peripheral tolerance. It can induce and promote Treg proliferation, inhibit monocytes activity, inhibit mast cell degranulation, and
also inhibit T cell activity.

shown that 20% of immature B cells downregulate the expres- of CD9, TIM-1, CD80, and CD86 have also been loosely
sion of BCR and actively carry out tolerance-induced editing. described. For example, Xiao et al [73] demonstrated in murine
Ongoing Ig light (L) chain gene recombination alters B cell models that TIM-1 not only regulates the production of IL-10
antigen specificity and in so doing, rescues auto‐reactive B cells by Breg cells but also is one of the main regulators of other
from deletion [59, 65–67]. If auto-reactive B cells not edited, or inhibitory cytokines and co-repressive molecules, such as Ebi3,
their heavy (H) chain features are not effectively corrected to GITRL, Fgl2, CLTLA-4, Lag3, and TIGIT. This also explains
L chain features, these cells may face apoptosis [68]. The con- why TIM-1-deficient B cells cause a more severe inflamma-
trol of apoptosis on B cell central tolerance is similar to that of tory response than those lacking TIGIT or IL-10 [73]. Despite
editing, which is incomplete. Through central tolerance, autore- this promising evidence, the role of TIM-1 is still unclear as a
active B cells will be regulated, resulting in the decrease of their marker of human Breg cells. Reportedly, there are about 40%
frequency in the B cell repertoire, their affinity for self-tissue, or of all Transitional B (TrB) cells express both TIM-1 and IL-10,
their functionality. Following this process, B cells will then enter and 90% of all TIM-1+ TrB cells express IL-10. In SLE patients,
the spleen, lymph nodes, or other tissues for further peripheral the expression of TIM-1 increased and correlated with IL-10
tolerance. It is accepted that B cell immune tolerance is achieved expression [74].
through the loss of autoreactive B cells, receptor editing, or
reduced cell viability/cell function.
11. Inhibitory cytokines
Breg cells can induce tolerance through their secretion of inhib-
10. Peripheral tolerance
itory cytokines. These cytokines traditionally encompass IL-10,
Regulatory B (Breg) cells play a key role in peripheral toler- and more recently IL-35 and TGF-β.
ance and can help maintain tolerance, limit ongoing immune
responses, and restore immune homeostasis. The role of Bregs in
suppressing the pathology associated with aggravating inflam- 11.1. Interleukin-10
matory responses in autoimmunity and transplant rejection has IL-10+ Breg cells can convert naïve T cells into Treg cells and
been consistently demonstrated, and recent studies have shown IL-10-secreting type-1 regulatory CD4+ T cells (Tr1). In addi-
that Bregs also play an important role in other diseases such as tion, they can also suppress immunogenic CD4+ T cells. These
infection, allergy, cancer, and chronic metabolic diseases [69, functions are intact in healthy people but are dysregulated in
70]. Unlike Treg cells that can be identified by markers such as those with immune diseases due to a reduced proportion of
Foxp3, Breg cells are not as easily identified, though their abil- IL-10+ Breg cells and impaired function. However, these func-
ity to secrete IL-10 remains one of the key factors that allow tions are enhanced in patients with chronic viral disease. In the
their identification [71, 72]. In addition to IL-10, expression mouse model of listeria infection, Horikawa et al [75] found
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that IL-10+ Breg cells can inhibit bacterial clearance by sup- antigen-presentation capacity and thus limiting the Th1/Th17
pressing macrophage function and CD4+ T cell proliferation. inflammatory response. A study involving B cell deficiency in
Furthermore, in a study of Mycobacterium tuberculosis infec- TGF-β transgenic mice demonstrated acceleration of experi-
tions, active tuberculosis is associated with high levels of active mental autoimmune encephalomyelitis development, which is
Breg cells and their inhibition of Th17 [76] thereby indicating related to the activation of myeloid DCs and increased Th1/
that an effective tuberculosis treatment would be associated Th17 responses in the central nervous system [94].
with a reduction in Breg cells [77]. In the case of patients with
an immunocompromised immune system (ie, SLE, RA, and type
1 diabetes), however, lower proportion of Breg cells results in an 11.3. Interleukin-35
inefficient inhibition of bacterial infection and viral clearance IL-35 can induce the conversion of B cells into the Breg subsets,
[78, 79]. though most experimental evidence is based on murine mod-
Although the immunosuppressive nature of Breg cells has els [54, 95]. Murine studies illustrated that EBI3 or IL-12p35
been vilified in cancer and viral and bacterial infections, Breg knock-out mice were unable to recover from experimental
cells play an important positive role in allergic disease, auto- autoimmune encephalomyelitis and experimental autoimmune
immunity, and improved transplantation tolerability [80, 81]. uveoretinitis (EAU), highlighting the importance of IL-35 cyto-
Desensitization immunotherapy in allergic patients causes kine. Progression of EAU was shown to be controlled by IL-35
increased IL-10+ Breg cells [82, 83]. Kim et al [84] demonstrated injection which resulted in the expansion of Breg cells in mice,
that increased IL-10 produced by Breg cells helps to inhibit the an increase in IL-10 and IL-35 production, and inhibition of
degranulation of murine mast cells, a crucial mechanism of Th1/Th17 inflammatory responses. Despite the benefit of IL-35
allergic disease. In studies of allergic airway disease and food injection for EAU, this resulted in the heightened risk of
allergy, again it has been demonstrated that IL-10-producing Salmonella typhimurium infection [96]. Studies in human have
Bregs not only suppress Th2 and Th17 inflammatory responses demonstrated that IL-35+ Bregs play a key role in promoting
but also promote Treg generation [85]. In transplantation, sev- tumor growth with their levels being upregulated in late-stage
eral studies have indicated that lower numbers of transitional gastric cancer [97] and pancreatic cancer [98]. In the context of
B cells or impaired suppressor function are associated with a autoimmune disease, IL-35+ Bregs and IL-35 in the peripheral
higher risk of renal transplant rejection [86]. Whereas, increased blood of patients with SLE displayed a more positive role in
proportions of IL-10+ Breg cells in patients have been associated which they negatively correlated with the disease activity index
with improved lung transplantation tolerance compared with [99]. Furthermore, decreased levels of IL-35 have also been
patients who develop chronic graft dysfunction [87]. Besides, demonstrated in patients with ankylosing spondylitis [100],
IL-10 Breg cells also exert mechanisms of tolerance to the fetus allergic asthma [100], and allergic rhinitis [54]. These highlight
during pregnancy in mice and humans, including the generation the importance of IL-35 and their potential use as a therapeutic
of tolerogenic DCs and Tregs and the reduction of Th17 cells target for multiple diseases.
[88, 89] shown to be important for maintaining the homeostasis
and successful pregnancy outcomes.
12. Immune tolerance as a therapeutic strategy
There are several immunotherapeutic strategies to treat diseases
11.2. Transforming growth factor-β arising from tolerance imbalance. A prime example of this is
TGF-β is a multifunctional cytokine that plays a vital role in allergen-specific immunotherapy (AIT), which consists of a
­
B cell regulation. Although TGF-β is mainly produced by Treg repeated administration of allergen extracts over several years,
cells, there is evidence that some Breg cells can also produce restoring tolerance and potentially eliminating the need for
TGF-β. Yang et al [90] categorized Breg cells into different sub- ­symptom-alleviating medication [101–103]. Adoptive cell ther-
types based on the gene expression profile. They found that apies using Tregs have shown promising preclinical and clinical
the expression of genes that promote TGF-β production was results for the treatment of autoimmune diseases, graft-versus-host
enriched in one subset, and they could activate the TGF-β path- disease, and transplantation [104–107]. Immunotherapy aims
way and IL-35-mediated pathway, but TGF-β+ Breg could not to restore or enhance the body’s natural tolerance mechanisms
produce IL-10 [90]. Further evidence shows that TGF-β pro- to achieve long-term control or even cure of disease. However,
duced by TGF-β+ Breg can induce naïve CD4+ T cells to differ- there are still challenges associated with the treatment, such as
entiate into Treg cells, thereby limiting T cell-related immune developing effective strategies to induce and maintain immune
responses. TGF-β in Treg-mediated gastrointestinal tract tolerance, identifying appropriate biomarkers to predict and
immunosuppression plays a key role [91] with TGF-β+ Breg monitor treatment responses, and managing potential side
cells being key players in the inhibition of Th2 inflammation effects of therapy.
through the influence of Tregs, thereby inhibiting colitis caused
by food allergy in mice. Similarly, mice infected with parasites
can also cooperate with anti-inflammatory macrophages to 13. Biomarkers of allergen-specific immunotherapy
suppress Th1 and Th2 inflammatory responses, thereby con- AIT remains the only disease-modifying treatment for aller-
trolling colitis. In respiratory diseases, TGF-β+ Breg cells have gic rhinitis, with tolerance induction observed in patients who
been found to be reduced in the alveoli of patients with intersti- receive treatment for a duration of 3 years or longer. While
tial lung disease [92]. In contrast, allergic airway inflammation AIT is effective in many patients, it is ineffective in a small
in mice can be controlled by transplanting TGF-β+ Bregs from proportion of patients, and it remains a challenge to stratify
hilar lymph nodes. In addition, it has been reported that TGF- these nonresponders from responders. Currently, there is no
β+ Breg-mediated hyporesponsiveness leads to anergy of CD4+ validated biomarker that can be used to measure desensiti-
and CD8+ T cells [93]. TGF-β+ Bregs can also induce immature zation, efficacy, and response to AIT, though several candi-
DCs to differentiate into tolerogenic DCs, leading to reduced date cellular biomarkers have been proposed with promising

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evidence. These biomarkers can be broadly categorized into in provocation testing, and the allergen exposure chamber. The
vitro biomarkers (ie, humoral, cellular, and metabolic) and in allergen exposure chamber is particularly useful for assessing
vivo biomarkers. the responses of patients to airborne allergens. By controlling
the concentration of allergen released, symptomatic changes
of patients across different allergen concentrations may be
14. T and B cells as in vitro cellular biomarkers of assessed [123]. However, the most widely used method is skin
allergen-specific immunotherapy prick testing (SPT). Proof of principle for this method was
Mechanisms of tolerance induction following AIT has been demonstrated by Moreno et al [124] and Sun et al [125], who
explored thoroughly and has been implicated with various observed statistically significant reductions in the size of SPT
modulation of the immune system that includes dampening of wheals in AR patients who underwent SCIT with DPT for 3
pro-allergic T cell responses (ie, Th2 and Tfh cells), immune years. Clinically, the utility of this method was demonstrated
deviation toward a Th1 response, induction of T and B regu- by Hajdu et al [126], who showed patients who underwent
latory cells and induction of neutralizing antibodies. Elevated AIT treatment for atopic dermatitis and AR showed both the
levels of natural and inducible Treg cells have been demon- absence of symptoms and concomitant negative SPT results
strated following a successful AIT [54, 108, 109]. In partic- [126].
ular, induction of natural Treg was observed in patients with
Japanese cedar pollinosis who received SLIT treatment [110]
17. Conclusion
while induction of iTreg was observed in grass pollen allergic
patients who received SLIT treatment [54]. Similarly, Breg cells Immune tolerance is an extremely complex immune process,
have also been shown to be induced following AIT. In a recent which is achieved through a complex network of mechanisms
study, induction of IL-10+ Breg cells was demonstrated follow- that prevent the immune system from attacking the body’s
ing a 3-week short course of Lolium Perenne immunotherapy own cells and tissues. These mechanisms include central and
[111, 112]. Furthermore, allergen-specific B memory cells have peripheral tolerance mechanisms which both have associ-
been reported to have an altered phenotype following AIT, ated advantages and disadvantages. These advantages include
with upregulated CD29 surface expression [113]. Though val- the prevention of autoimmune disease, allergy, and transplant
idation via clinical trial is required to further confirm these rejection. While major drawbacks include the exploitation of
observations, Treg and Breg cells possess tolerogenic proper- tolerogenic mechanisms in cancer, creating an immunosup-
ties that may indicate their suitability as potential biomarkers pressive microenvironment, and aiding disease progression.
of AIT. Deepening our knowledge of immune tolerance mechanisms
not only provides us with a greater understanding of underlying
disease mechanism and progression, but also unveils a pleth-
15. Humoral biomarkers ora of immune pathways that may be exploited for therapeutic
The success of AIT may also be assessed by monitoring the lev- advancement.
els of different Ig classes. These humoral biomarkers include
total and specific IgE, IgG, and IgA subclasses. Although widely Conflicts of interest
used to diagnose allergic patients, changes in specific IgE levels
do not correlate well with clinical response and therefore are The authors have no financial conflicts of interest.
not a validated for assessment of efficacious AIT [114–116].
A better, but still imperfect, tool of assessment is IgG1, IgG2, Author contributions
and IgG4 levels. Mechanistically, IgG2 and IgG4 likely help
regulate allergic responses through neutralizing allergens rather Xun Meng prepared the initial draft of the review. Mohamed
than immune activation due to their reduced capacity to acti- H. Shamji provided the outline of the review. Janice A. Layhadi,
vate effector cells. Indeed, the observed success of IgG blocking Sean T. Keane and Natanya J.K. Cartwright reviewed, amended
activity in vitro, investigated using IgE-facilitated allergen bind- and provided feedback to the manuscript.
ing assays, has made IgG one of the more promising humoral
biomarkers of AIT success [117]. However, although IgG sub- References
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