Does TCR signaling have to be so exhausting? The T cell adaptor Gads skews CD8 T cells towards exhaustion 2259399

Abstract Introduction Cytotoxic T lymphocytes (CTL) may limit tumor growth by responding to neoantigens. Yet within the tumor, chronic antigen recognition triggers a hyporesponsive state (exhaustion), in which multiple immune checkpoints repress CTL activity. Downstream to the TCR, a cascade of tyrosine kinases triggers the assembly of a signalosome, nucleated by three adaptor proteins, SLP-76, LAT and Gads. Whereas LAT and SLP-76 are absolutely required for TCR responsiveness, Gads performs a modulatory role, encompassing both positive and negative regulatory functions. Rationale TCR signaling is a key driver of tumor immunity; yet also induces exhaustion. We propose to uncouple these responses, by moderate perturbation of the TCR signaling pathway. Methods We inducibly deleted Gads in developmentally normal OT-1 T cells. Gads-deficient T cells were clearly marked by the expression of tdTomato. OT-1 T cells were then expanded and differentiated ex vivo, under conditions of acute or chronic exposure to their cognate antigen. Results Gads was largely dispensable for the antigen induced proliferation and differentiation of OT-1 T cells into perforin- and granzyme-expressing CTL. Upon restimulation, Gads-deficient OT-1 CTL matched or exceeded wild type cells in antigen induced degranulation, production of cytokines, and killing of OVA-expressing target cells. Remarkably, deletion of Gads appeared to render the cells exhaustion resistant. Following chronic antigen stimulation the frequency of PD-1 hi - TIGIT hi cells was markedly reduced in Gads-deficient OT-1 CTL, whereas the PD-1 lo - TIGIT lo population markedly increased. Conclusion Our data strongly support the possibility of uncoupling antigen-induced effector functions from antigen-induced exhaustion. Funding Source The Israel Science Foundation Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)