A STAT5 activator drives a CD8+ memory T cell fate in the absence of cytokine 4012

Abstract Description The ability of memory CD8+ T cells to self-renew and persist over many years is critical to achieving long-term protection from pathogens and efficacious cancer immunotherapies. The formation of memory CD8+ T cells requires a differentiation process that is regulated by cytokine-induced JAK-STAT signaling pathways. However, these cytokine signals are often dysregulated in cancer which results in T cell dysfunction. We therefore developed a strategy to activate endogenous STAT5 in the absence of cytokine. Our STAT5 activator (aSTAT5) enables CD8+ T cell survival and function without cytokine. To determine how aSTAT5 affects T cell differentiation, we performed bulk RNA sequencing and compared aSTAT5 to the cytokines IL-2 (effector) and IL-7/IL-15 (memory). Our results, supported by qPCR, indicate that aSTAT5 CD8+ T cells have a memory-like fate with decreased expression of effector and exhaustion related genes, and that this state is maintained over days. aSTAT5 also recapitulated the metabolic state of memory T cells, as determined by Seahorse assays. Following acute LCMV infection, we observed markedly increased aSTAT5 T cells in comparison to cytokine cultured controls in the blood, spleen, and lymph nodes at 45 days post-infection, consistent with increased memory T cell formation. Overall, our findings reveal that aSTAT5 can drive a memory CD8+ T cell fate, which provides a therapeutic rationale for direct activation of STAT5 to augment CD8+ T cell therapies. Funding Sources Supported by Rogel Cancer TrEC Graduate Scholarship; NCI T32CA009676; NIGMS R35. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)