T cell dysfunction in Activated PI3K δ Syndrome explained by cell intrinsic and extrinsic components

Abstract Activated PI3K Delta Syndrome (APDS) is a rare condition caused by heterozygous gain of function mutations in PIK3CD, which encodes the leukocyte-restricted p110δ catalytic subunit of phosphoinositol 3-kinase (PI3K). PI3K is activated downstream of many T cell receptors and has been implicated in the control of CD4+ T cell helper differentiation, activation and proliferation. APDS patients have increased PI3K activity that leads to several immune manifestations including lymphoproliferation, Th2-related pathologies and impaired Ab responses. Analysis of a CRISPR/Cas9 mouse model (Pik3cdE1020K) showed a decreased frequency of naïve and a concurrent increase in memory T cells and Tfh cells, indicating T cell hyperactivation, as well as changes in cytokine expression and T cell help. Our studies investigated CD4+ T cell intrinsic and extrinsic alterations contributing to the dysregulation of the immune response. We identified cell intrinsic features resulting in increased IL-4 and IL-5, explaining the Th2 mediated disease in these patients. Additionally, cell intrinsic changes in Tfh generation and function were shown in the in vivo mouse model, contributing to an impaired ability to sustain GCs and alter isotype switching. Furthermore, additional studies have shown that the overactive T cells result from both intrinsic and extrinsic factors, with contributions from both dysregulated T cells and B cells exerting effects on T cell activation. Together, these studies reveals an important role of PI3K in modulating T cell differentiation and function through both T cell-intrinsic and extrinsic mechanisms. This provides new insights into the APDS pathophysiology with potential to improve the clinical management of these patients.