DOCK8 regulates protective immunity by controlling the function and survival of RORγt+ ILCs

Nat Commun. 2014 Aug 5:5:4603. doi: 10.1038/ncomms5603.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Bone Marrow Cells / cytology
  • Cell Survival
  • Citrobacter rodentium
  • Colon / immunology
  • Colon / metabolism
  • Enterobacteriaceae Infections / immunology*
  • Female
  • Guanine Nucleotide Exchange Factors / immunology*
  • Interleukin-17 / metabolism
  • Interleukin-22
  • Interleukins / metabolism
  • Interleukins / pharmacology
  • Lymphocytes / immunology*
  • Lymphocytes / microbiology
  • Male
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Phosphorylation
  • Sequence Analysis, RNA

Substances

  • Dock8 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Interleukin-17
  • Interleukins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Rorc protein, mouse

Associated data

  • GEO/GSE58765