CD137 signals program the TCR⍺β+ CD8⍺⍺ intraepithelial lymphocyte population for survival 2139

Abstract Description A population of TCRαβ+ CD8αα Intraepithelial Lymphocytes (IEL) reside in the intestine and perform regulatory roles. While most developing αβ T cells that experience agonist signals in the thymus are deleted as a central tolerance mechanism, thymic precursors of TCRαβ+ CD8αα IEL (IELp) require agonist TCR signals for selection, however, other signals that promote the generation of this unique intestinal T cell population are not fully understood. To gain insight into gene expression differences that underly IELp selection, we completed a trajectory analysis of thymic IELp using scRNA-seq and flow cytometry. We identified CD137, a costimulatory receptor in the TNF receptor superfamily, as a candidate for contributing to IELp maturation. CD137 was expressed on both thymocytes with a gene expression profile characterizing clonal deletion and IELp selection. CD137 was upregulated during thymic IELp development and maintained in the periphery on the most highly self-reactive IELp. Analysis of CD137-deficient mice and competitive mixed bone marrow chimeras supported a role for CD137 in generating CD8αα IEL but not thymic IELp maturation, nor in upregulating of trafficking molecules needed to enter the intestinal epithelium. However, in vitro culture with IL-15 suggested a survival defect in CD137-deficient IEL. Taken together, our data suggest that the most highly TCR signaled IELp receive CD137 signals that program them for long-term survival as intestinal residents. Funding Sources Supported by a CIHR Project Grant. Topic Categories Hematopoiesis and Immune System Development (HEM)