Lymphocyte apoptosis and impaired type-17 immunity underlie mucosal candidiasis in DOCK8 deficiency and can be rescued by IL-7 immunotherapy

Up to two-thirds of DOCK8-deficient patients develop chronic mucocutaneous candidiasis (CMC), yet the mechanistic basis for this susceptibility remains elusive. Here, we utilized a mouse model of oral candidiasis to investigate the cellular and molecular mechanisms that drive CMC susceptibility in DOCK8 deficiency.

We demonstrate that DOCK8 promotes mucosal fungal clearance via the induction of protective type-17 immune responses. Mechanistically, in the absence of DOCK8, the accumulation of IL-17+ and IL-22+ TCRαβ T cells, γδ T cells, and innate lymphoid cells (ILCs) was markedly decreased in the oral mucosa, driven by increased apoptotic cell death, not impaired cell proliferation or recruitment from the blood. Unexpectedly, DOCK8 was required for the cell-intrinsic acquisition of a type-17 phenotype only in oral mucosal γδ T cells, but not in TCRαβ T cells or ILCs in vivo.