Rescue of self-reactive B cells by provision of T cell helpin vivo

Cook, Matthew C.; Basten, Antony; Groth, Barbara Fazekas de St

doi:10.1002/(sici)1521-4141(199808)28:08<2549::aid-immu2549>3.0.co;2-o

Cited by 42 publications

(22 citation statements)

References 37 publications

(53 reference statements)

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“…One point to be kept in mind when interpreting studies on the role of T-cell help in reversing B-cell anergy is the availability of T-cell help relative to the timing of self-antigen-induced signalling. Cook et al 50 have shown that T-cell-derived signalling must be available soon after self-antigen-induced signals are delivered to the B cells to prevent the induction of anergy.…”

Section: Decreased Lifespanmentioning

confidence: 99%

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

et al. 2007

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Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. Multiple transgenic mouse models have enabled the dissection of mechanisms that underlie anergy, and recently, anergic B cells have been identified in the periphery of wild-type mice. Heterogeneity of mechanistic concepts developed using model systems has complicated our understanding of anergy and its biological features. In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles.The generation of B cells occurs throughout life and proceeds through several distinct stages and checkpoints (FIG. 1). After birth, B-cell generation occurs in the bone marrow, where cells progress through pro-B-cell and pre-B-cell stages of development. At the next stage (as immature B cells), they acquire antigen specificity by virtue of expression of a functional Bcell receptor (BCR); this is also the first key specificity checkpoint in B-cell development. Cells that successfully traverse this phase enter the periphery as transitional B cells.The ability of the adaptive immune system to provide protection against pathogens requires a diverse BCR repertoire that can recognize a broad range of foreign proteins. Diversity is generated early in development by random rearrangement of immunoglobulin genes. This inevitably results in the genesis of receptors that recognize self antigens. It is estimated that 75% of human early immature B cells are self-reactive 1 . About a third of these self-reactive immature B cells are purged from the repertoire by receptor editing, wherein renewed immunoglobulin gene rearrangement generates a new light chain to pair with the existing immunoglobulin heavy chain in an anthropomorphic effort to generate a non-self-reactive © 2007 Nature Publishing Group Correspondence to J.C.C. cambierj@njc.org. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Immunol. Author manuscript; available in PMC 2013 July 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript BCR 2,3 . Failing this, these B cells are deleted by apoptosis 4 . Despite these mechanisms of central tolerance, many self-reactive B cells escape to the periphery where they are silenced by an induced state of unresponsiveness known as anergy (BOX 1). Anergy can be viewed as nothing more than the state of lethargy that ensues when B cells mount a normal initial response to antigen but fail to receive secondary signals that sustain their activation. Paradoxically, the maintenance of anergy requires chronic binding of antigen and signal transduction, yet the stimulation of unoccupied receptors fails to trigger signal transduction pathways that are...

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Section: Decreased Lifespanmentioning

confidence: 99%

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

et al. 2007

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“…DCs have been shown to both positively and negatively regulate autoantibody production [5][6][7]. Helper T cells, or signals associated with T-cell help, appear to negatively regulate B-cell tolerance [8][9][10][11][12]. It remains unclear as to which helper T-cell populations can support autoantibody production.…”

Section: Introductionmentioning

confidence: 99%

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

et al. 2012

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The maintenance of B-cell anergy is essential to prevent the production of autoantibodies and autoimmunity. However, B-cell extrinsic mechanisms that regulate B-cell anergy remain poorly understood. We previously demonstrated that regulatory T (Treg) cells are necessary for the maintenance of B-cell anergy. We now show that in Treg-cell-deficient mice, helper T cells are necessary and sufficient for loss of B-cell tolerance/anergy. In addition, we show that the absence of Treg cells is associated with an increase in the proportion of CD4 + cells that express GL7 and correlated with an increase in germinal center follicular helper T (GC-T FH ) cells. These GC-T FH cells, but not those from Tregcell-sufficient hosts, were sufficient to drive antibody production by anergic B cells. We propose that a function of Treg cells is to prevent the expansion of T FH cells, especially GC-T FH cells, which support autoantibody production.Keywords: anergy r autoimmunity r B cells r T FH r Treg cells Supporting Information available online IntroductionThe production of autoantibodies due to loss of B-cell tolerance is central to the development of autoimmunity. Our understanding of the mechanisms that maintain B-cell tolerance, especially B-cell anergy, remains poorly defined. The absence of regulatory T (Treg) cells results in the development of IPEX, a fatal disease associated with the development of significant autoantibodies and autoimmunity [1,2]. The development of autoantibodies suggests that Treg cells play a key role in regulating B-cell tolerance, a statement supported by our previous study showing a role for Treg cells in the maintenance of B-cell anergy [3].Numerous signaling molecules have been identified whose absence prevents the establishment or maintenance of B-cell Correspondence: Dr. Stephen B. Gauld e-mail: sgauld@mcw.edu anergy at the intrinsic level (reviewed in [4]). However, our understanding of B-cell extrinsic mechanisms that regulate B-cell anergy remains poor. DCs have been shown to both positively and negatively regulate autoantibody production [5][6][7]. Helper T cells, or signals associated with T-cell help, appear to negatively regulate B-cell tolerance [8][9][10][11][12]. It remains unclear as to which helper T-cell populations can support autoantibody production.Follicular helper T (T FH ) cells are defined based on their expression of the chemokine receptor CXCR5, the transcription factor Bcl6, and play an essential role in providing help to B cells, promoting antibody production [13][14][15]. However, a role for T FH cells in the production of autoantibodies is less well defined. The expansion of T FH cells is known to be associated with a lupus-like disease in sanroque mice and CD4 + cells from the sanroque model support antichromatin autoantibody production in an adoptive transfer system [16,17]. A study by Simpson et al. [18] In our study, we use the Foxp3 DTR mouse model [20] to deplete the complete Treg-cell population in adult hosts and show that Treg cells are essential to prevent th...

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“…Nevertheless, such cells may be rescued, activated, and expanded if provided with Th cell help (13), a feature that also was found for anergic B cell responses of other autospecificities (14,15). However, in contrast to B cells, it is unclear what specificity Th cells may have in cognate interactions with dsDNA-specific B cells.…”

mentioning

confidence: 98%

Idiotype-Specific Th Cells Support Oligoclonal Expansion of Anti-dsDNA B Cells in Mice with Lupus

Aas-Hanssen

Funderud

Thompson

et al. 2014

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is marked by a Th cell–dependent B cell hyperresponsiveness, with frequent germinal center reactions and hypergammaglobulinemia. The specificity of Th cells in lupus remains unclear, but B cell Ids have been suggested. A hallmark is the presence of anti-dsDNA, mutated IgG autoantibodies with a preponderance of arginines in CDR3 of the Ig variable H chain (IgVH). B cells can present V region–derived Id peptides on their MHC class II molecules to Id-specific Th cells. We show that Id-specific Th cells support the proliferation of anti-dsDNA Id+ B cells in mice suffering from systemic autoimmune disease with SLE-like features. Mice developed marked clonal expansions of B cells; half of the IgVH sequences were clonally related. Anti-dsDNA B cells made up 40% of B cells in end-stage disease. The B cells expressed mutated IgVH with multiple arginines in CDR3. Hence, Id-driven T cell–B cell collaboration supported the production of classical anti-dsDNA Abs, recapitulating the characteristics of such Abs in SLE. The results support the concept that Id-specific Th cells may trigger the development of SLE and suggest that manipulation of the Id-specific T cell repertoire could play a role in treatment.

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Rescue of self-reactive B cells by provision of T cell helpin vivo

Cited by 42 publications

References 37 publications

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

Idiotype-Specific Th Cells Support Oligoclonal Expansion of Anti-dsDNA B Cells in Mice with Lupus

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