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

Background: 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.

Objective: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4 T-cell function.

Methods: 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.

Results: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (T) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human T cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a T cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4 T cells also acquired an aberrant T 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 cells was largely CD4 T-cell extrinsic, whereas changes in cytokine production and T cell function were cell intrinsic.

Conclusion: 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.