Regulation of Tfh function in autoimmunity by TSLP

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Project Summary Germinal centers (GCs) are dynamic immune microarchitectures that expand in secondary lymphoid organs during infection or immunization. GCs can also develop in the absence of overt immunization or detectable adventitious infection (called spontaneous GCs, Spt-GCs). As opposed to induced GCs that form during immunization or anti-pathogen responses, Spt-GCs develop in response to endogenous antigens and contribute, in part, to chronic autoimmunity. Spt-GCs are enlarged and more frequent in autoimmune-prone mice in the absence of detectable pathogens or overt immune challenge. Spt-GCs exhibit a linear correlation with nuclear-reactive autoantibody titers in lupus-prone mice and many GC B cells isolated from Spt-GCs developed in SLE-prone mice are autoreactive. Both Tfh cells and CGC B cells within the Spt-GCs play essential roles in regulating high-affinity autoantibody production. Spt-GCs have also been detected in patients with several different autoimmune diseases including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Sjogren’s syndrome (SS) and Type 1 diabetes (T1D). For example, pediatric SLE patients have elevated numbers of circulating pre- GC B cells and adult SLE patients exhibit increased circulating Tfh cells. These data indicate the important roles that Spt-GCs play in pathogenic autoantibody production. While the correlation of Spt-GCs with autoimmunity is clear, the factors that control their development remain obscure. We have found that the cytokine thymic stromal lymphopoietin (TSLP) plays a significant role in the development of Spt-GCs. TSLP- and TSLPR-deficient mice have dramatically reduced numbers of Spt- GCs, and those that exist appear to be vestigial. Consistent with this observation, we have also found that TSLP signaling is critical for the differentiation of Tfh. Taken as a whole, these data demonstrate an important role for TSLP in Spt- and induced-GC formation and function. We will test this hypothesis by determining the role of TSLP in Tfh development and function (Aim 1), and determine the role of Tfh-specific TSLP signaling in autoimmune prone mice.