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 signaling, 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.

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

“…tially novel function of DOCK8 in protective immunity by regulating the generation, survival, and function of RORγt + innate lymphoid cells (27). Thus, DOCK8 deficiency affects a wide range of immune cells, which hampered our understanding of the precise function of DOCK8 in particular types of immune cells.…”

Interleukin 23 in IBD Pathogenesis

“…Although very rare in the circulation, in the intestinal lamina propria, Rorγ + ILC3s are enriched and constitute up to 8% of lymphocytes and ~70% of ILCs in the murine intestinal LP [39]. ILC3s include fetal LTi cells and adult ILC3s [130].…”

“…Unlike nonpathogenic Th17 cells, which express only IL-17, IL-23-activated pathogenic Th17 cells express IFN-γ and GMCSF in addition to the IL-17. Various lines of evidence suggest that Th17 cells, and hence IL-23R signaling, is critical for the development of chronic inflammatory conditions such as Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematous (SLE) in addition to MS. [38][39][40]. ILC3s express IL-23R and depend on IL-23 for their production of various effector cytokines including IL-22, IFN-γ and IL-17, which take part in the abovementioned processes.…”

DOCK8 regulates signal transduction events to control immunity

“…In addition, DOCK8-deficient ILC3s could not phosphorylate STAT5 as efficiently as wild type cells in response to IL-7. 34 These ILCs also had a higher rate of spontaneous apoptosis, again linking DOCK8 to the apoptotic program. It will be interesting to determine if DOCK8 is regulating cell death through the modulation of co-stimulation signals within the immune synapse, leading to enhanced activation-induced cell death, or whether there is a more direct link to cell death induction, as suggested by reduced Bcl2 levels in NKT cells.…”

“…DOCK8 is also essential for the function and survival of RORγt+ innate lymphoid cells (ILCs). 34 The scarce ILCs in DOCK8-deficient mice following Citrobacter rodentium infection are also less responsive to IL-7-and IL-23-induced signaling, leading to defective IL-22 release. Diminished IL-22 release occurred through sub-optimal STAT3 activation in the absence of DOCK8.…”