Abstract
Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease involving the production of a wide range of autoantibodies and complement activation. The production of these high-affinity autoantibodies requires T cell/B cell collaboration as well as germinal center (GC) formation. T follicular regulatory cells (TFRs) are functional specialized T regulatory cells (Tregs) that safeguard against both self-reactive T and B cells. However, recent evidence suggests that TFRs are not always stable and can lose Foxp3 expression to become pathogenic “ex-TFRs” that gain potent effector functions. In this review, we summarize the literature on intrinsic and extrinsic mechanisms of regulation of TFR stability and discuss the potential role of TFR reprogramming in autoantibody production and SLE pathogenesis.
Highlights
Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease with wide clinical heterogeneity
In a fate-mapping experiment involving Forkhead Box P3 (Foxp3) bacterial artificial chromosome (BAC) transgenic mice expressing GFP-Cre under the control of the Foxp3 promoter, we demonstrated that a fraction of T regulatory cells (Tregs) are not stable
Benoist et al found that Foxp3+ Treg cells are unstable in NZW mice, which may explain the reduced sensitivity of this NZW Tregs to limiting doses of trophic cytokines, IL-2 and -33 [102]
Summary
Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease with wide clinical heterogeneity. The autoantibodies from lupus patients are high affinity, somatic mutated, and class switched, and their generation requires the formation of germinal centers (GCs) with assistance from follicular helper T cells (TFHs) [7] In addition to their involvement in GC formation, TFHs, a unique CD4+ subset of T cells with high expression of Bcl, PD-1, and CXCR5, Stability of TFRs play a major role in the selection of high-affinity B cells. TFHs have emerged as a critical immunoregulator of antibody production as well as the pathogenesis of human SLE [8] Another small population of CD4+ T cells, regulatory T cells (Tregs), maintain self-tolerance by suppressing both autoreactive T and B lymphocytes through the production of inhibitory cytokines such as IL-10, TGF-b, and IL-35 [9, 10]. A specific subtype of TFHs, SOSTDC1+ TFHs, promote TFR cell differentiation by inhibiting the b-catenin pathway through the secreted protein SOSTDC1 [56]
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