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

Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal-recessive immunodeficiency disorder that manifests with hyper-IgE syndrome and susceptibility to viral, bacterial, fungal, and parasitic infections as well as malignancy, atopy, and autoimmunity. 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. Concordantly, mice with conditional DOCK8 deletion in all RORγt-expressing IL-17-producing lymphoid cells, but not in CD4+ T cells alone, were susceptible to oral candidiasis. Moreover, prophylactic administration of the gc family cytokine IL-7 rescued lymphocyte apoptosis, increased the number of IL-17+ and IL-22+ cells, and promoted fungal clearance in DOCK8-deficient mice. Thus, we show that mucosal candidiasis in DOCK8 deficiency is driven by multicellular defects in lymphocyte survival and accumulation resulting in impaired type-17 immunity. IL-7 immunotherapy boosts mucosal type-17 responses and ameliorates fungal susceptibility.