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 receptors expressed by T cells 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 with some of the most common features being lymphoproliferation, respiratory tract infections, Th2-related pathologies, and impaired antibody 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. We have previously shown cell-intrinsic alterations in PI3K GOF CD4+ T cells resulting in increased IL-4 and IL-5 (explaining the Th2 mediated disease in these patients) and changes in Tfh function (that contribute to an impaired ability to provide help to germinal centers B cells). In contrast, we determined that the overactive T cells result from extrinsic factors.
Here we set out to determine what drives this increased T cell activation. We determined that multiple cell types, including T and B cells, exert effects on different aspects of T cell activation.
Together, these studies reveal an important role of PI3K in modulating T cell differentiation, activation, and function through both T cell-intrinsic and extrinsic mechanisms. In particular, an improved understanding of T cell hyperactivation can provide insight into the lymphoproliferation that affects a substantial proportion of APDS patients. Overall, this study has the potential to dissect the mechanisms underlying disease, providing grounds to define new drug targets and ultimately improve the clinical management of these patients.