Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4⁺ T cells.

Abstract

Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8⁺ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4⁺ T cells in disease pathogenesis. We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4⁺ T-cell function. We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4⁺ T cells and a novel murine disease model caused by overactive PI3K signaling. PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (T_FH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human T_FH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a T_FH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4⁺ T cells also acquired an aberrant T_FH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and T_FH cells was largely CD4⁺ T-cell extrinsic, whereas changes in cytokine production and T_FH cell function were cell intrinsic. Our studies reveal that CD4⁺ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.