DOCK8 regulates protective immunity by controlling the function and survival of RORγt+ ILCs
Copyright policy )DOCK8 regulates protective immunity by controlling the function and survival of RORγt+ ILCs
Retinoic acid receptor-related orphan receptor-γt-positive (RORγt(+)) innate lymphoid cells (ILCs) produce interleukin (IL)-22 and IL-17, which are critical for protective immunity against enteric pathogens. The molecular mechanism underlying the development and survival of RORγt(+) ILCs is not thoroughly understood. Here, we show that Dedicator of cytokinesis 8 (DOCK8), a scaffolding protein involved in cytoskeletal rearrangement and cell migration, is essential for the protective immunity against Citrobacter rodentium. A comparative RNA sequencing-based analysis reveals an impaired induction of antimicrobial peptides in the colon of DOCK8-deficient mice, which correlates with high susceptibility to infection and a very low number of IL-22-producing RORγt(+) ILCs in their GI tract. Furthermore, DOCK8-deficient RORγt(+) ILCs are less responsive to IL-7 mediated signalling, more prone to apoptosis and produce less IL-22 due to a defect in IL-23-mediated STAT3 phosphorylation. Our studies reveal an unsuspected role of DOCK8 for the function, generation and survival of RORγt(+) ILCs.
- University of Mary United States
- University of Washington United States
- University of Washington Department of Immunology United States
- Benaroya Research Institute United States
- Washington State University United States
Male, Mice, Knockout, Cell Survival, Colon, Sequence Analysis, RNA, Interleukins, Interleukin-17, Enterobacteriaceae Infections, Apoptosis, Bone Marrow Cells, Nuclear Receptor Subfamily 1, Group F, Member 3, Interleukin-22, Article, Mice, Animals, Citrobacter rodentium, Guanine Nucleotide Exchange Factors, Female, Lymphocytes, Phosphorylation
Male, Mice, Knockout, Cell Survival, Colon, Sequence Analysis, RNA, Interleukins, Interleukin-17, Enterobacteriaceae Infections, Apoptosis, Bone Marrow Cells, Nuclear Receptor Subfamily 1, Group F, Member 3, Interleukin-22, Article, Mice, Animals, Citrobacter rodentium, Guanine Nucleotide Exchange Factors, Female, Lymphocytes, Phosphorylation
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