Immune regulation of naturally occurring self-reactive Tfh-like CD4+ T cells 3068

Abstract Description Despite multiple tiers of tolerance, the peripheral repertoire of mice and humans harbors self-reactive CD4+ conventional T cells capable of triggering autoimmunity. In recent work, we identified a population of CD4+ T cells that exhibit overt reactivity to self-antigens and spontaneously adopt a T follicular-helper (Tfh)-like signature at steady state. The identification of these naturally occurring Tfh-like (nTfh) cells delineates a previously unappreciated cell fate for self-reactive CD4+ T cells. Given that nTfh cells express hallmarks of active TCR signaling at homeostasis and are mobilized to non-lymphoid organs following Treg cell depletion, we hypothesize that nTfh cells require constraint by extrinsic and/or intrinsic factors. Consistent with this, short-term depletion of Tregs is sufficient to trigger mobilization of nTfh clones to non-lymphoid sites, where they persist following return to homeostasis. Additionally, antibody-mediated blockade of PD-1/PD-L1 or CRISPR/Cas9-mediated deletion of Pdcd1 in nTfh cells results in significant expansion of nTfh clones in vivo, demonstrating that the PD-1/PD-L1 axis is crucial for the constraint of nTfh cells. Ongoing work will leverage a high-throughput CRISPR/Cas9-based in vivo screen to identify additional T cell-intrinsic factors required for the constraint of nTfh cells. Our findings are expected to identify key nodes of extrinsic and intrinsic regulation that control this unique self-reactive T cell subset. Funding Sources Supported by Immunology Training Grant T32-AI007090; Nancy Mollin Michael Endowment; NIH U01-AI154560 Topic Categories Basic Autoimmunity (BA)