DOCK8 regulates protective immunity by controlling the function and survival of ROR?t+ ILCs.

ABSTRACT: Retinoic acid receptor-related orphan receptor-?t-positive (ROR?t(+)) 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 ROR?t(+) 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 ROR?t(+) ILCs in their GI tract. Furthermore, DOCK8-deficient ROR?t(+) 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 ROR?t(+) ILCs.

SUBMITTER: Singh AK 

PROVIDER: S-EPMC4135384 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature