PI3K GOF leads to dysregulation of T and B cells that both contribute to extrinsically driving activation and differentiation of other CD4+ T cells.

Abstract

Activated PI3K delta syndrome 1 (APDS1) is caused by a heterozygous germline gain-of-function (GOF) variant in PIK3CD, which encodes the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K). APDS1 patients display a broad range of clinical manifestations and perturbations in cellular phenotype. One of the most striking features is the dysregulation of the T-cell compartment, characterized by an increase in memory T cells, including Tfh cells, and a concomitant decrease in naïve T cells. We have previously shown that many of these changes in T-cell populations were T-cell extrinsic and were also induced in WT T cells that developed in the presence of PI3K GOF cells. Here we dissected the drivers of dysregulated T-cell activation using a mouse model of APDS1. This revealed that PI3K GOF macrophages and DCs made little contribution to the aberrant T-cell activation. Instead, PI3K GOF T cells were able to drive the loss of WT naïve CD4⁺ T cells, while dysregulated PI3K GOF B cells mediated an increase in Tfh cells. Surprisingly, despite previous reports of increased PI3K signalling driving dysregulated inflammatory Tregs, we saw no evidence for Pik3cd GOF Tregs acquiring an inflammatory phenotype and driving T-cell activation. These studies provide new insights into the role of PI3K in immune cells and how increased PI3K can drive T- and B-cell dysregulation and contribute to the phenotype of APDS1 patients.