Mechanisms of Immune Regulation of Self-Reactive CD4+ T Cells

Multiple layers of tolerance in the immune system aim to eliminate or control CD4+ conventional T (Tconv) cells reactive to self-antigens. Despite this, the natural immune repertoire harbors self-reactive CD4+ Tconv cells capable of subverting constraint and promoting the development of autoimmunity. Notably, the specific factors and cell types that dictate the alternate fates and suppression of self-reactive CD4+ Tconv cells remain incompletely understood. This dissertation examines the processes coordinating self-reactive CD4⁺ T cell constraint in two T cell populations and the implications for maintaining tolerance. First, we built upon previous work that identified Tconv cell clones exhibiting unique features, including overt reactivity to self-antigens and adoption of a T follicular-helper (Tfh)-like phenotype, referred to as naturally occurring Tfh-like (nTfh) cells. Here, we demonstrate that nTfh cells rapidly adopt a Tfh-like phenotype via interaction with CD11c-expressing cells in the periphery. Transient release from Foxp3⁺ regulatory T cell (Treg)-mediated constraint or PD-1 blockade/inactivation led to expansion of nTfh cells, demonstrating that these cells require ongoing suppression. A CRISPR/Cas9-based screen identified additional cell-intrinsic factors required for nTfh constraint, including Roquin-1 and A20. Second, in a T cell model with defined antigen specificity, we examined how peripheral antigen exposure shapes the balance between self-reactive Treg and Tconv cells. Cognate-antigen encounter under inflammatory conditions revealed that self-reactive Tconv cells remain responsive and can expand, with evidence of Treg erosion following repeated challenge. Notably, this Tconv expansion did not result in overt tissue pathology, suggesting additional layers of tolerance. Collectively, our results demonstrate that extrinsic and intrinsic regulation converge to enforce immune tolerance of self-reactive CD4+ T cells. Future work may elucidate the roles of peripheral antigen sensing and acquisition of the nTfh phenotype in shaping autoimmune responses.