title: DOCK8 regulates protective immunity by controlling the function and survival of RORγt+ ILCs.
abstract: 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.
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington 98101, USA.
authors.forename: Akhilesh K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington 98101, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Eken
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington 98101, USA.
authors.forename: Mallory
authors.initials: M
authors.lastname: Fry
authors.affiliation: Benaroya Research Institute, Immunology Program, Seattle, Washington 98101, USA.
authors.forename: Estelle
authors.initials: E
authors.lastname: Bettelli
authors.affiliation: 1] Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington 98101, USA [2] Department of Immunology, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D002470:Cell Survival; D044082:Citrobacter rodentium; D003106:Colon / Q000276:immunology / Q000378:metabolism; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000276:immunology*; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism*; D010766:Phosphorylation; D017423:Sequence Analysis, RNA; D000097043:Interleukin-22
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000097043:Interleukin-22; C545324:Dock8 protein, mouse; C539901:Rorc protein, mouse
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