PI3Kδ: a key driver of effector differentiation under conditions of T cell exhaustion

Abstract

Abstract In chronic infection and cancer, prolonged antigen exposure drives a state of T cell hyporesponsiveness, called exhaustion. A small subset of TCF1 +progenitor exhausted stem-like T cells (pTex) cells, is required to maintain exhausted T (Tex) cells and respond to checkpoint blockade. Understanding mechanisms regulating these populations may help identify approaches to counter exhaustion. Phosphatidylinositol 3-kinase-d (PI3Kd) is an important component of T cell signaling. We have found that TCF-1 is repressed in CD8 +T cells from patients with Activated PI3K Delta Syndrome and in a mouse model (Pik3cd E1020K/+mice) in acute viral infections. How activated-PI3Kδ affects T cell exhaustion is unknown. Using chronic LCMV clone 13 infection, we found that Pik3cd E1020K/+mice rapidly die, yet surviving mice recover faster than WT. RNA sequencing revealed decreased expression of Tcf7, encoding TCF-1, in antigen-specific CD8 +T cells, along with loss of TCF-1 +Tim3 −CD8 +pTex cells in Pik3cd E1020K/+mice upon cl13 infection. Tex cells that were maintained during chronic infection in Pik3cd E1020K/+mice displayed an effector-like phenotype, with expression of CX3CR1 +and KLRG1 +, and increased effector functions, suggesting that these cells might induce early immunopathology yet increase viral clearance. P14 cell transfers, in conjunction with CRISPR-mediated gene disruption, revealed that loss of FoxO1 leads to loss of TCF-1 +cells, whereas the increase of effector cells is at least partially cell-extrinsic. Our findings suggest that PI3Kδ is a critical rheostat that balances effector vs exhaustion differentiation, providing insight for therapeutic strategies for exhaustion.