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

Abstract

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...

B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis

“…Thus, Fas-expressing B cells interacting with FasL on responder T cells provide a target for Treg to govern humoral immune responses. This is consistent with previous data indicating that Treg control of B cells is entirely dependent upon the presence of responder T cells 12. Our data also show that the provenance of the responder T cells (healthy or RA) did not alter the outcome of suppression.…”

“…Treg can limit autoreactive B cell responses in mice: Treg removal results in aberrant autoantibody production and worsens arthritis in susceptible models, whereas Treg administration reverses these effects 9–11. FoxP3-deficient mice exhibit altered B cell development and a failure in B cell anergy 12. In the absence of Treg, B cell loss of tolerance was driven by responder T cells 12.…”

“…FoxP3-deficient mice exhibit altered B cell development and a failure in B cell anergy 12. In the absence of Treg, B cell loss of tolerance was driven by responder T cells 12. In fact, self-perpetuating B/responder T cell interactions play a key role in systemic autoimmune disease 13.…”

Control of Germinal Center Responses by T-Follicular Regulatory Cells

“…The relatively subtle effects of specific Tfr depletion stand in considerable contrast to the large effects seen when Tregs as a whole are depleted (11, 12). Equally, while the most highly-differentiated Tfr lack CD25 expression, anti-CD25 antibody is capable of inducing substantial autoantibody production (10).…”

“…When we identified Tregs on the basis of their CD25 expression we found that anti-CD25 depletion of Tregs lead to strong induction of autoantibodies against parietal cells in the stomach epithelia, and against thyroglobulin proteins produced by thyroid follicular cells (10). While CD25 is not entirely exclusive to Tregs, specific depletion of Tregs via diphtheria toxin in mouse models in which Tregs express the primate diphtheria toxin receptor leads to strongly-enhanced GC formation, Tfh cell expansion and antibody responses (11, 12). Loss of control over humoral immunity is also characteristic of mutations of Foxp3 in the scurfy mouse strain and in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome patients, and leads to the production of autoantibodies, hyper IgE and strongly-enhanced GC/Tfh responses (12–18)…”