Both T and B cells contribute to dysregulated activation and differentiation of CD4+T cells in Activated PI3K delta syndrome 1

Abstract

AbstractActivated PI3K delta syndrome 1 (APDS1) is caused by a heterozygous germline gain-of-function (GOF) variants inPIK3CDwhich 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 characterised 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 PI3K GOF macrophages and DCs made little contribution to the aberrant T cell activation. Instead, the loss of naïve T cells was mostly driven extrinsically by PI3K GOF T cells, while the increase in Tfh cells was mediated by dysregulated PI3K GOF B cells. Surprisingly, despite previous reports of increased PI3K driving dysregulated inflammatory Tregs, we saw no evidence forPik3cdGOF Tregs acquiring an inflammatory phenotype and driving T cell activation. These studies provide new insights into the clinical phenotype of patients with APDS1 and new understanding of the role of PI3K in immune cells.