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

Abstract

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