The eATP receptor P2RX7 promotes the establishment of progenitor exhausted CD8+ T cells and optimal response to checkpoint blockade during chronic viral infection 3251

Abstract Description Persistent exposure to antigens and immunosuppressive signals in tumors or chronic infections drives CD8+ T cell exhaustion (Tex), a programmed state of T cell dysfunction. While efforts have been made to combat Tex through immunotherapies, they often fail to induce lasting protective effects. Exhausted CD8+ T cells consist of various subsets with distinct transcriptional, functional, and metabolic features. Among these subsets, progenitor exhausted CD8+ T cells (Tprog) are important: they are metabolically quiescent, retain stemness capacity and respond better to checkpoint blockade therapy (e.g., anti-PD1). Here, we report that, in response to chronic viral infection (LCMV Clone 13), P2RX7 is crucial for the establishment of Tprog cells. P2RX7-KO CD8+ T cells had decreased numbers of Tprog cells. P2RX7-KO Tprog cells lose metabolic quiescence, displaying increased glycolytic function and loss of mitochondrial respiration dependence. Our meta-analyses of gene (scRNAseq) and protein (LegendScreen assay) expression suggest that P2RX7-KO Tprog cells undergo abnormal exhaustion differentiation paths, and express reduced levels of integrin beta-1 (ITGB1), a molecule associated with lymphoid residency of Tprog cells. Finally, we found that P2RX7 is crucial for exhausted CD8+ T cells to respond to anti-PD1 in vivo. These data open the possibility of using P2RX7 agonism to boost the efficacy of existing checkpoint blockade immunotherapies aimed to revitalize CD8+ T cell responses. Funding Sources NIH Grants K99/R00A139381 and R01A170649 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)