mTOR signaling mediates ILC3-driven immunopathology

Abstract

Innate lymphoid cells (ILCs) have a protective immune function at mucosal tissues but can also contribute to immunopathology. Previous work has shown that the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1) is involved in generating protective ILC3 cytokine responses during bacterial infection. However, whether mTORC1 also regulates IFN-γ-mediated immunopathology has not been investigated. In addition, the role of mTORC2 in ILC3s is unknown. Using mice specifically defective for either mTORC1 or mTORC2 in ILC3s, we show that both mTOR complexes regulate the maintenance of ILC3s at steady state and pathological immune response during colitis. mTORC1 and to a lesser extend mTORC2 promote the proliferation of ILC3s in the small intestine. Upon activation, intestinal ILC3s produce less IFN-γ in the absence of mTOR signaling. During colitis, loss of both mTOR complexes in colonic ILC3s results in the reduced production of inflammatory mediators, recruitment of neutrophils and immunopathology. Similarly, treatment with rapamycin after colitis induction ameliorates the disease. Collectively, our data show a critical role for both mTOR complexes in controlling ILC3 cell numbers and ILC3-driven inflammation in the intestine.

Dietary butyrate, lauric acid and stearic acid improve gut morphology and epithelial cell turnover in weaned piglets

“…Interestingly, our results showed that the diets supplemented with BT, LA and SA all increased ileal p-mTOR activation and positive Ki67 cells/crypts in the ileum compared with the control diet. This suggests that p-mTOR may improve intestinal morphology by increasing the proliferation of epithelial cells, a result similar to that of Teufel et al. (2021) .…”

Characteristics of tRNA-Derived Small RNAs and microRNAs Associated with Immunocompromise in an Intrauterine Growth-Restricted Pig Model

“…The mTOR signaling pathway [ 69 ], endocytosis and autophagy [ 70 ] are related to immune function in mammals. The functional enrichment analysis of these two small RNA produced similar results.…”

Innate Lymphoid Cell Plasticity in Mucosal Infections

“…In turn, mitochondrial ROS support prolonged activation of HIF-1α, further amplifying IL-22 and IL-17 production by ILC3s [ 113 ] ( Figure 3 ). Interestingly, mTOR signaling controls ILC3 homeostasis in the small intestine but not in the colon, probably due to higher mTOR signaling in ILC3s in the small intestine compared to the colon [ 119 ]. Moreover, IFNγ production by ILC3s was dependent on mTORC1 and mTORC2 signaling in the small intestine, whereas IL-22 production by ILC3s was only dependent on mTORC1, suggesting distinct mechanisms of IL-22 and IFNγ activation in different ILC3 subsets [ 119 ].…”