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Originally published online as doi:10.1189/jlb.0507310 on July 26, 2007

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(Journal of Leukocyte Biology. 2007;82:1033-1039.)
© 2007 by Society for Leukocyte Biology

The role of B cells in the induction of peripheral T cell tolerance

Hossam M. Ashour*,1 and Tarek M. Seif{dagger}

* Department of Microbiology and Immunology, Faculty of Pharmacy, and
{dagger} Department of Surgery, Kasr-El-Aini Medical School, Cairo University, Cairo, Egypt

1 Correspondence: Faculty of Pharmacy, Cairo University, Department of Microbiology and Immunology, Cairo 11562, Egypt. E-mail: hossamking{at}mailcity.com

Key Words: antigen presentation • deletion • suppression • anergy


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INTRODUCTION
 
The immune system of vertebrates is designed to protect against invading pathogens. To be able to deal with different antigenic threats, the T cell repertoire is very diverse. This diversity, though useful, can cause autoimmune diseases if any imbalances in the function of the immune system occur. However, the immune system has its own mechanisms for suppressing or regulating the potentially dangerous, autoreactive T cells. The first mechanism is central tolerance, where potentially self-reactive thymocytes, which encounter APC expressing self-encoded molecules, are triggered to undergo apoptosis so that the thymocytes are clonally deleted in the thymus. However, thymic deletion of self-reactive T cells seems only to affect cells of the highest affinity, and some autoreactive T cells (with low affinity to self-molecules) still manage to gain access to the periphery [1 , 2 ]. Furthermore, only T cells, which recognize antigens expressed within the thymus, are clonally deleted. This means that T cells, which are capable of recognizing tissue-restricted antigens, can still manage to make it to the periphery [2 ]. To deal with the threat posed by these self-reactive T cells, there are mechanisms for induction of peripheral T cell tolerance.

Tolerance can be defined as the state of unresponsiveness to a specific antigen as a result of the presence of one or more mechanisms, which suppress the immune reaction. Thus, tolerance is an active process and is not just the absence of an immune response. B cells are professional APC, which activate or tolerize T cells to help induce or suppress immune responses. There are several mechanisms by which B cells induce tolerization of the T cell compartment. Identifying how peripheral T cell tolerance can be induced will serve to design new therapeutic strategies for regulating the balance between tolerance and active immunity in cases such as autoimmune diseases, tumor immunity, and transplant tolerance.


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MODES OF INDUCING T CELL TOLERANCE
 
B cells use different mechanisms to induce T cell tolerance, as depicted in Figure 1 . B cells can induce tolerance of the CD8+ T cell compartment directly or indirectly. Direct tolerance develops when CD8+ T cells directly recognize antigen presented on B cells through MHC class I (#6 in Fig. 1 ). This can lead to deletion or anergy of the T cell compartment. It can also lead to the development of CD8+ T suppressor cells (active suppression). Conversely, there are at least five ways in which B cells can influence the development of T cell tolerance indirectly (numbered from 1 to 5 in Fig. 1 ). First, B cells can present antigen in a tolerogenic manner through MHC class II to antigen-specific CD4+ Th cells, leading to the generation of tolerant CD4+ Th cells, which cannot provide help for CD8+ T cells. Second, B cells can inhibit proliferation and differentiation of CD4+ Th cells. Third, persistence of antigen presentation by B cells can lead to a tolerogenic rather than an immunogenic response. Fourth, B cells can regulate the DC activity (via IL-10 or antibodies), conferring on DC the ability to induce tolerogenic responses. Fifth, B lymphocytes can secrete suppressive factors, which have a direct inhibitory effect on Th cells or CTL.


Figure 1
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  		Figure 1. Different mechanisms used by B cells to induce T cell tolerance. 1, CD4 +Th cells directly recognize antigen presented on tolerogenic (Tol.) B cells via MHC class II. 2, Tolerogenic B cells inhibit proliferation and/or differentiation of CD4 +Th cells. 3, Persistence of antigen presentation by B cells tolerizes CD4 +T cells. 4, Tolerogenic B cells regulate the DC activity by secreting IL-10 or antibodies. 5, Tolerogenic B cells secrete suppressive factors to inhibit CD4 +Th cells or CD8+ T cells. 6, CD8+ T cells directly recognize antigen presented on tolerogenic B cells via MHC class I.


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DIRECT INDUCTION OF T CELL TOLERANCE BY ANTIGEN PRESENTATION TO CD8+ T CELLS
 
Deletion
One mechanism by which B cells can induce tolerance directly is through deletion of CD8+ T cells, as proposed by Bennett et al. [3], who demonstrated that B cells tolerized antigen-specific CD8+ T cells directly via CD95-mediated, activation-induced deletion. The direct tolerogenic effect on CD8+ T cells was indicated by the weak OVA257–264-specific CTL response to OVA + CFA (CD4+ T cell-independent response) in mice previously challenged with OVA257–264-coated B cells [3 ]. The deletional tolerance mechanism was indicated by the loss of activated OT-I cells after recognition of antigen on B cells in contrast to the protection of activated OT-I.lpr T cells (lacking CD95) from death [3 ]. This mechanism was supported by studies of Townsend and Goodnow [4 ], who demonstrated an abortive proliferation (continuous proliferation in the presence of continuous death) of CD4+ T cells induced by antigen presentation by rare B cells in vivo. A recent study by Werner-Klein et al. [5 ] demonstrated that T cell tolerance can be achieved by retrovirally altered B cells (expressing a transcriptionally targeted antigen in thymus, lymph nodes, and spleen), which can directly induce clonal deletion of CD8+ T cells in vivo. In addition, the authors showed that B cells induced anergy of the CD8+ T cell population.

Anergy
A second scenario of a direct tolerogenic effect of B cells on CD8+ T cells is through T cell unresponsiveness, also known as T cell anergy. Anergic T cells are defined as T cells with an increased activation threshold or cells unable to respond to the same antigen, even in the presence of intense costimulation [6 , 7 ]. Furthermore, anergic T cells can act as suppressor cells in vitro and in vivo [8 , 9 ]. In several studies, activated B cells presented antigen on MHC class I to antigen-specific T cells, causing them to develop into tolerant T cells [5 , 10 11 12 13 ]. For example, LPS-treated male B cells but not dendritic cells (DC) introduced into female mice induced in vivo CTL tolerance (demonstrated by a decrease in CTL responses and prolonged skin graft survival) to the male-specific minor antigen H-Y via B cell antigen presentation [10 ]. Likewise, in vitro activation of B cells with LPS induced T cell anergy via TGF-β1 expression on the surface of the B cells [14 ]. Using MHC I antigen presentation, B cells induced anergy in a CD8+ T cell clone by its cognate antigen [15 ].

In all of the previous experiments, B cells expressed costimulatory molecules and yet, induced T cell tolerance [10 11 12 13 14 15 ]. This seems to contradict reports that attribute the ability of B cells to induce T cell tolerance to the absence of B cell costimulatory activity in accordance with the Danger model [11 , 16 17 18 19 20 21 22 ]. In the Danger model, immunogenic APC express costimulatory molecules in response to a danger signal and thus, are capable of activating T cells [23 ]. However, if these danger signals are absent, then costimulatory molecules are not up-regulated on APC; therefore, the responding T cells are tolerized instead of being activated [23 ].

Taking all these results together, it appears that the absence of costimulation is not the only factor that drives tolerance. In other words, increasing the expression of costimulatory molecules on tolerogenic B cells does not necessarily enable B cells to present antigen in an immunogenic manner. Another plausible explanation is that certain Th1 cell clones might have fewer requirements for costimulatory activity [24 ]. In this case, experimental results obtained using such clones will not be similar to the responses obtained using other Th1 clones or naïve T cells, which may need stronger costimulatory signals [24 ]. Similarly, Th1 and Th2 CD4+ T cells were shown to have different costimulatory requirements [25 26 27 28 ]. Thus, during the generation of antigen-specific Th1 or Th2responses, adjuvants can induce differential costimulation in antigen-specific B cells, which may subsequently affect T cell polarization [29 ]. A third explanation can be derived from the work of Raimondi et al. [30 ], who showed that chronic antigen presentation induced tolerance of antigen-specific T cells, whether antigen presentation was done by resting or activated B cells. Accordingly, chronic antigen presentation per se can induce T cell tolerance, regardless of the state of activation of the B cells [30 ].

Active suppression
Qa-1 is a nonclassical MHC class I molecule, which is expressed at higher levels in activated B and T lymphocytes [31 ]. It contributes to immune regulation by stimulating the CD8+ T cells [31 ]. The work of Noble et al. [31 ] suggested that activated B cells used their antigen-presentation capacity via the Qa-1 molecule to induce the generation of CD8+ T suppressor cells. These suppressor cells inhibited Th2 cells, thus reducing IgM and IgG production in response to cellular or viral antigen [31 ]. Following studies in other models indicated that the generation of CD8+ T suppressor cells required B cells expressing an intact, functional β2m molecule [32 , 33 ]. A lack of functional β2m, as in β2m–/– mice, means that the mice lack cell surface expression of classical and nonclassical MHC I molecules, including the Qa-1 molecule and thus, contain few mature CD8+ T cells [31 ].


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INDIRECT MODE OF INDUCING T CELL TOLERANCE
 
Antigen presentation to CD4+ T cells
Many reports demonstrated that tolerogenic B cells presented antigen on MHC class II to CD4+ T cells, inducing CD4+ T cell tolerance via deletion, anergy, or active suppression [4 , 11 , 13 , 18 , 19 , 34 35 36 37 38 39 40 41 ]. In accordance with that, Watt et al. [19 ] recently reported that the expression of MHC class II on resting B cells inhibited tumor immunity induced by DC vaccination by inducing T cell tolerance. If CD4+ T cell tolerance develops, the help of CD4+ Th cells to CD8+ T cells will be disabled. Thus, CD8+ T cell tolerance ensues. The following sections cite examples of each of the mechanisms, which can lead to the induction of CD4+ T cell tolerance.

Deletion
B cells contribute to tolerance by inducing apoptosis of the CD4+ T cells. Townsend and Goodnow [4 ] demonstrated that upon recognition of antigen presented on rare B cells, CD4+ Th cells were deleted following an initial proliferation. Similarly, Tian et al. [42 ] showed that B cells, expressing Fas ligand (FasL) and secreting TGF-β, induced apoptosis of Th1 autoimmune cells.

Anergy
Gilbert and Weigle [11 , 37 ] noticed that resting B cells treated with F(ab')2 goat anti-mouse IgM for 24 or 48 h, in the presence or absence of LPS, induced a dramatic decrease in the antigen-specific, proliferative capacity of Th1 cells. This work indicated that B cells had the capacity to induce antigen-specific anergy in the CD4+ Th cell compartment via antigen presentation [11 , 37 ]. The ability of B cells to present antigen in a tolerogenic manner was also required for the development of antigen-specific CD4+ T cell anergy in a model of oral tolerance to aeroallergens [13 ]. Based on their role in the induction of oral and nasal tolerance [13 , 43 , 44 ], it is probable that the presence of B cells in some areas of the body, such as the gut or nasal mucosa, may make the B cells more prone to inducing T cell tolerance, as long as they receive the antigen in a tolerogenic context. However, the B cells themselves were primed and not tolerized in a model of orally induced T cell tolerance [45 ].

Active suppression
As APC, B cells contribute to tolerance by inducing the generation or mediating the function of CD4+ T regulatory cells (Tregs). In a model of i.v.-induced T cell tolerance, Valujskikh et al. [46 ] demonstrated that i.v. injection of high doses of a minor transplantation antigen [β-galactosidase (β-gal)] did not lead to β-gal skin graft tolerance in a recipient B cell knockout (KO) mice. The reason was that B cells were required as APC for mediating the suppressive function of Tregs, as was the case with tolerant mice [46 ]. Thus, Tregs needed B cells to be able to inhibit the CD8+ T cell-mediated graft rejection in an antigen-specific manner [46 ]. In addition, Reichardt et al. [47 ] reported recently that naïve B cells induced the de novo generation of nonclassical CD4+ CD25+ Tregs, which did not express the transcription factor forkhead box p3. B cells were also required for the induction of Tregs in a model of T cell tolerance elicited by the injection of antigens into the anterior chamber of the eye [33 , 41 , 48 , 49 ]. In the aforementioned model of anterior chamber-associated immune deviation, marginal zone splenic B cells needed to coexpress MHC class II and MHC class Ib (Qa-1) simultaneously to induce the generation of antigen-specific CD4+ CD25+ Tregs and CD8+ Tregs, respectively [33 ].

Inhibiting proliferation and differentiation
B cells can induce T cell tolerance by suppressing proliferation and/or differentiation of CD4+ T cells. Mature B cells, with up-regulated B7-2 costimulatory molecules, inhibited the proliferation of self-reactive effector CD4+ T cells via the CD40/CD40L interactions in inflammatory bowel disease [50 ]. In addition, endogenous B cells were required to limit the differentiation of expanded, autoreactive CD4+ T cells and to down-regulate the TCR expression on effector T cells in systemic, autoimmune reactions [51 ].

Persistence of antigen presentation
Raimondi et al. [40 ] argued that the persistence of antigen presentation by B cells is one of the main conditions for inducing peripheral T cell tolerance. Whereas chronic antigen presentation by B cells had a tolerogenic effect, leading to antigen-specific CD4+ T cell tolerance, transient antigen presentation by B cells led to CD4+ T cell activation and memory formation [40 ]. In accordance with the hypothesis that self and nonself are changing properties of the individual [52 ], the authors speculated that the slow rate of change associated with persistent antigen presentation in the case of self-antigen was what induced T cell tolerance [40 ]. Conversely, nonself antigens were immunogenic because of a rapid rate of change [40 ]. This report supported some earlier data, which indicated the development of T cell tolerance as a result of persistent antigen presentation [53 , 54 ].

Regulatory effect of B cells on DC
B cells can regulate the antigen-presenting function of DC, causing the DC to induce a more tolerogenic response. For example, Montagnoli et al. [55 ] reported a failure to generate IL-10-producing DC in B cell KO mice, which caused a subsequent failure to generate CD4+ CD25+ Tregs. In addition, lymph node B cells activated with IL-10, or UV irradiation inhibited DC induction of immune responses [56 ].

Role of IL-10
Moulin et al. [57 ] reported an increased production of IL-12 by DC in B cell KO mice. This correlated with an impaired capacity to induce antigen-specific differentiation of IL-4-secreting T cells following adoptive transfer to control recipient mice [57 ]. By presumably promoting IL-10 secretion, B cells down-regulated IL-12 secretion from DC, causing a Th1 response to be shifted toward a Th2 response [57 ]. By contrast, the lack of B cells in µMT (B cell KO) mice impaired the ability of DC to promote IL-4 secretion [57 ]. Likewise, peripheral blood T cells of X-linked a-{gamma}-globulinemia patients, who lack peripheral, circulating B cells, showed a preferential Th1 profile of Th cell responses [58 ]. The role of IL-10 secretion by B cells was also emphasized in a murine model of oral tolerance [43 ]. In this model, B cell-derived IL-10 enhanced the tolerogenic capacity of DC [43 ].

Role of antibodies
In addition to IL-10 secretion, antibodies can mediate the regulatory effect of B cells on DC. Barcy et al. [59 ] showed that B cells secreted antibodies, which cross-linked the FcR on DC. This caused severe impairment of the antigen-presenting function of DC, so that they could no longer stimulate T cell activation efficiently [59 , 60 ]. For example, hepatitis B Ig-inhibited DC needed to stimulate T cells, which mediate acute rejection after liver transplantation [60 ]. Thus, treatment with Igs offered a potential maneuver for protection against acute rejection, which can follow liver transplantation [60 ]. Using the same principle, i.v. Ig (IVIg; a therapeutic Ig preparation obtained from pools of plasma of healthy blood donors [61 ]) or even IVIg-treated cells were successfully used to suppress excessive immune responses in immune thrombocytopenic purpura by signaling through the activating Fc{gamma}Rs on DC [62 ].

This induction of DC regulatory activity can be attributed to the formation of soluble immune complexes between Igs and the inhibitory Fc{gamma}R on DC [62 , 63 ]. It can also be attributed to the inhibitory effect of Igs on the differentiation and maturation of human DC and on the ability of mature DC to secrete IL-12, while enhancing their IL-10 production [64 , 65 ]. A similar observation was made in a model of experimental autoimmune encephalomyelitis (EAE) when engagement of Fc{gamma}R on DC by Igs led to tolerogenic antigen presentation and production of IL-10 [66 ].

Suppressive factors secreted by B cells
B cells can secrete suppressive factors, which induce T cell tolerance. These suppressive factors may inhibit the CD8+ T cell compartment and/or the CD4+ T cell compartment.

An example of a factor that regulates the CD8+ T cell compartment is IgG, linked to latent TGF-β (IgG-TGF-β). B cell-derived IgG-TGF-β was shown to prevent primary CTL responses in an antigen-nonspecific manner [67 , 68 ]. In this model, manipulations that led to dissociation of IgG and latent TGF-β or inactivation of the active form of TGF-β abolished suppression [68 ]. Accordingly, the authors postulated that IgG-TGF-β was taken up through FcRs for IgG, followed by the cleavage of the active form of TGF-β from the latent TGF-β [68 ].

An example of a factor that regulates the CD4+ T cell compartment is IL-10, which when secreted by B cells, regulated autoimmunity by tolerizing Th1 cell responses that mediate EAE or rheumatoid arthritis [69 , 70 ].

It is noteworthy that the tolerogenic antigen presentation by B cells to the T cell compartment may be beneficial (or protective) or nonbeneficial to the host.


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BENEFICIAL TOLERANCE
 
In a model of EAE, B cell antigen presentation induced a beneficial, Th2-like T cell response, which controlled the concomitant, encephalitogenic Th1 reaction to the auto-antigen [71 ]. Similarly, activated antigen-specific B cells had a critical, beneficial role in inducing CD4+ T cell anergy to inhaled aeroallergens, thus conferring protection against the development of allergic sensitization [13 ].


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NONBENEFICIAL TOLERANCE
 
In a tumor immunity model, B cells inhibited induction of CTL-mediated tumor immunity because of disabled CD4+ T cell help required for CTL-mediated tumor immunity [39 ]. The presence of B cells promoted a polarized, nonprotective Th2 humoral immune response instead [39 ]. Qin et al. [39 ] interpreted these data by a competition between B cells and other APC for antigen. Accordingly, it could be hypothesized that B cells presented antigen in a tolerogenic manner to CD4+ T cells. This disabled the CD4+ T cell help, which is normally required for CD8+ T cells to be primed. Thus, T cell tolerance was induced, although the CTL themselves were not affected directly by the antigen-bearing B cells.


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ARE B CELLS DISPENSABLE FOR INDUCING T CELL TOLERANCE?
 
The view that B cells are mandatory for the induction of peripheral T cell tolerance was challenged by several observations made in µMT mice [72 73 74 75 76 77 ]. Studies by Phillips et al. [72 ] demonstrated that a single injection of deaggregated human {gamma}-globulin (DHGG) induced antigen-specific T cell tolerance in µMT mice. This indicated that B cells are dispensable as APC for the induction of antigen-specific T cell tolerance in their model [72 ]. Likewise, Baird and Parker [73 ] demonstrated that low doses of a soluble protein antigen (deaggregated OVA) induced T cell tolerance, whether in normal or µMT mice. Tolerance in the previous models was evidenced by diminished T cell proliferation and the lack of cytokine secretions upon secondary challenge [72 , 73 ]. Moreover, Vella et al. [74 ] demonstrated that class II-restricted T cell tolerance to soluble peptide (as manifested by the inability to respond to peptide challenge) and to super-antigen (as manifested by T cell death) can be induced in µMT mice. Similarly, other studies showed that the absence of B cells in µMT mice did not affect the generation of T cell tolerance to orally administered antigen [76 , 77 ]. Seidel-Guyenot et al. [75 ] also noticed that the lack of B cells in µMT mice did not affect T cell priming in low-zone tolerance to contact allergens and contact hypersensitivity.

It is noteworthy that all of the aforementioned studies, which showed that B cells were dispensable for inducing T cell tolerance, were performed on µMT mice. Although µMT mice lacked IgM or IgD expression, they were shown to contain IgA+ B cells [78 ]. In addition, µMT mice were reported to have low levels of {kappa}-chain rearrangements [79 ]. Thus, we cannot exclude the possibility that the contaminating IgA+B cells or the {kappa}-chain rearrangements affected the results in the previous reports. This possibility is supported further by the work of Tsitoura et al. [13 ], who used B cell-deficient mice with a targeted mutation in the JH gene but without any contaminating IgA+ B cells (JHD mice) [80 ] to demonstrate that B cells are crucial for inducing T cell tolerance to aeroallergens. One other concern when using µMT mice is the impairment of the T cell compartment, which is manifested by defective T cell responses following viral infections in µMT mice [81 82 83 ].

The apparent contradiction between reports, which showed the requirement of B cells, and other reports, which showed the dispensability of B cells for the induction of T cell tolerance, can be reconciled in several ways. First, the development of T cell tolerance in the absence of B cells in a few animal models does not exclude a role for B cells in inducing T cell tolerance in other models. B cells may even contribute to tolerance in the same models but under different conditions. Therefore, reports showing that B cells were not required for inducing tolerance can only be used to disprove the hypothesis that "T cell tolerance is solely dependent of B cell antigen presentation" and the hypothesis that "only B cell antigen presentation (of extremely low or extremely high antigen doses) induces tolerance, whereas all other professional APC (presenting moderate antigen doses) are immunogenic" [84 85 86 ].

Second, the apparent conflict in results might be related to the mode of antigenic stimulation of the B cells (form, dose, and localization of the antigen) [84 , 86 , 87 ]. For example, DHGG induced tolerance, whereas aggregated HGG induced immunogenicity [72 ]. Similarly, B cells activated with LPS induced T cell tolerance, whereas B cells activated with anti-Ig and anti CD40-activating antibody induced immune T cell responses [14 ]. Moreover, the route of antigen administration might also have influenced results. This is supported by the work of Adorini et al. [88 ], who demonstrated that the mode of antigen administration determined preferential presentation of peptide-class II complexes by DC or B cells.

Other factors, which might have affected T cell responses in the previous models, include mouse strain variations, the cytokine milieu in which the cells reside, and the surrounding microenvironment during the initial encounter of the B cells with the T cells. A relevant hypothesis would be that the response of the same APC to different cues in different conditions would be different. In one scenario, the APC can be stimulated to induce an immunogenic T cell response. In a different scenario, the same APC can be stimulated to elicit a tolerogenic T cell response. The aforementioned hypothesis is supported by the work of Finkelman et al. [89 ], which indicated that depending on the conditions, DC can present antigen in vivo in a tolerogenic or immunogenic manner. It is further supported by the work of Voigtlander et al. [90 ], which demonstrated that DC could be transformed from a tolerogenic into an immunogenic APC, depending on the surrounding cues. One of these cues necessary for a tolerogenic antigen presentation is the persistence of the antigen as in the case of chronic antigen presentation by B cells [30 ].


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B CELL TOLERANCE
 
Besides their role in regulating T cell tolerance discussed in this review, B cells themselves can be induced to undergo B cell tolerance, which can be achieved by clonal deletion [91 , 92 ], receptor editing [93 , 94 ], or anergy [95 ] (which ultimately leads to deletion [96 ]). These mechanisms appear to operate mostly in immature, rather than mature, B cells. Tolerance achieved through these mechanisms is critical for protection against autoimmune diseases, which can be caused by unchecked, autoreactive B cells.


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CONCLUDING REMARKS
 
This review sheds light on a variety of mechanisms used by B cells to induce peripheral T cell tolerance. It has implications about why patients with deficiencies in the B cell compartment can develop aberrant T cell responses. The intent is to focus on the roles of B cells, implying that B cells should come to mind when one thinks about manipulating T cell tolerance in vaccination or treatment strategies. Taking advantage of each of these mechanisms can have significant effects on the protection and treatment of different immune-mediated diseases. Thus, different immune-mediated interventions can be used to improve healthcare. For example, inducing donor-specific T cell tolerance can lead to higher transplant-acceptance rates. Understanding how T cell tolerance develops can help design better tumor vaccination strategies. Inducing allergen-specific T cell tolerance can help us design new vaccination strategies and therapies for allergic diseases and asthma.

In all of the previous examples, B cells can be conditioned to help tolerize or stimulate the T cell compartment. This idea relies on the antigen-presenting capacity of B cells to the T cell compartment. B cells can be pulsed in vitro, under tolerizing conditions, with the specific autoantigen (in the case of autoimmune diseases), allergen (in the case of allergic diseases), or alloantigen (in the case of transplantation) and then reinjected into the subject to be able to induce an antigen-specific T cell tolerance. Conversely, antigen-pulsed B cells, subjected to stimulating conditions, can be used to induce an immunogenic response of the antigen-specific T cell compartment in the design of tumor vaccines. Thus, it is important to perform studies that define a "stimulating" versus "tolerizing" condition under which an antigen-presenting B cell interacts with a T cell to cause immunity or tolerance.

Received May 19, 2007; revised June 27, 2007; accepted June 29, 2007.


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