PI3Kdelta coordinates transcriptional, epigenetic and metabolic changes to promote effector CD8 T cells differentiation.

Abstract Activated PI3K-delta syndrome (APDS) is a primary immunodeficiency caused by heterozygous activating mutations of PIK3CD, resulting in dysregulated immunity, recurrent infections and lymphoproliferation, yet underlying mechanisms behind these phenotypes remain unclear. Using patient samples Pik3cd E1020K/+mouse model, we evaluated CD8 cell function both vitro response to infectious agents, assessing cellular phenotypes, metabolism, gene expression chromatin organization. E1020K/+CD8 cells exhibited accelerated differentiation short-lived effectors, associated with increased mTORC1 c-Myc pathways, as well altered metabolic, transcriptional epigenetic circuits characterized pronounced IL-2/STAT5 signature heightened IL-2 responses that prevented IL-15 memory-like cells. Moreover, failed sustain proteins critical for maintenance long-lived memory cells, including TCF1, mounted inadequate central vivo enhanced generation effector populations. In chronic LCMV Clone 13 infection, E1020K/+mice rapidly die, the surviving mice recover more than WT counterparts. fail TCF1 +Ly108 +stem-like simultaneous reduction exhausted However, also have an expansion CX3CR1 +effector viral clearance immunopathology. Our data position PI3Kd hub integrating multiple signaling nodes promote T program during acute infections. This work was supported Intramural Research Program NIAID NHGRI, NIH.