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 herpes virus 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: 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 patient CD4+ T cells and a novel murine disease model due to overactive PI3K signaling.

RESULTS: PI3K overactivation caused substantial increases in memory and T follicular helper (Tfh) cells, and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human Tfh cells had dysregulated phenotype and function, characterized by increased PD1, CXCR3, and IFNγ expression - the phenotype of a Tfh subset with impaired B-helper function. This was confirmed in vivo where Pik3cd GOF CD4+ T cells also acquired an aberrant Tfh-phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in both memory and Tfh cells was largely CD4+ T cell extrinsic while changes in cytokine production and Tfh 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.