Regulation of T cell-mediated T1D: The role of T follicular helper cells - SUMMARY/ABSTRACT T follicular helper cells (Tfh) are recognized as critical regulators of antibody (Ab) responses. Consequently, Tfh in autoimmunity have primarily been studied for their role in regulating autoantibody production. However, Tfh are also linked to T cell-mediated autoimmune diseases such as type 1 diabetes (T1D). Evidence suggests a role for Tfh in T1D. For example, elevated levels of Tfh correlate with the development of diabetes in at-risk individuals, and NOD mice that lack expression of IL-21, the signature cytokine of Tfh, are protected from insulitis and diabetes. Despite these and other findings, whether and how Tfh regulate effector T cell (Teff)- mediated events leading to b cell destruction, and the properties of diabetogenic Tfh, remain poorly understood. It is also unclear if regulatory Tfh (Tfr) suppress the diabetogenic response. To address these fundamental questions, we propose three Specific Aims. Aim 1 tests the hypothesis that islet Tfh undergo both qualitative and quantitative changes as T1D progresses, leading to a Tfh pool with enhanced diabetogenic potential. Aim 2 focuses on defining the role and mechanisms of islet Tfh in regulating b cell autoimmunity. We hypothesize that islet Tfh mediate destructive insulitis during late-stage preclinical T1D by sustaining the pathogenic function of islet Teff. Conversely, Tfr limit islet Teff function indirectly by directly suppressing islet Tfh. Aim 3 will test the hypothesis that a hierarchy exists among islet Tfh subsets in their diabetogenic function, which is dependent on T-bet expression. This proposal is expected to provide novel insights into the properties, roles and mechanisms of Tfh and Tfr in regulating T cell-mediated b cell autoimmunity.
