Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.
A certain number of epithelial cells in intestinal crypts are DNA damage resistant and contribute to regeneration. However, the cellular mechanism underlying intestinal regeneration remains unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1+) are right above Lgr5high cells in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1+ cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1+ cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5high radiosensitive crypt base columnar stem cells (CBCs). This enables an efficient repopulation of the intestinal epithelium at early stage when Lgr5high cells are not emerging. Furthermore, relative to CBCs, Msi1+ cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1+ cells are cycling ISCs that maintain and regenerate the intestinal epithelium.
CD4 T-cell responses to gut microbiota are crucial in regulating intestinal inflammation. Whereas T helper (Th)1 and Th17 cells reactive to gut microbiota are central to the pathogenesis of inflammatory bowel disease (IBD), regulatory T cells (Treg) inhibit it. CD4 T-cell metabolism is highly dynamic. T-cell activation demands biosynthetic precursors and adequate energy for effector function.1 Metabolic reprogramming of T effector cells and Treg cells leads to distinct metabolic programs. If activated T cells fail to induce appropriate metabolic pathways, effector function and the ability to induce or inhibit inflammatory disease are impaired.
Abstract Irregular CD4+ effector T cell responses play an essential role in the intestinal inflammation, while IL-10 produced by effector T cells limits their pathogenesis to maintain the intestinal homeostasis. Dietary free fatty acids are actively involved in regulating immune responses, and mammalian G protein-coupled receptor (GPR) 120, a receptor for long-chain fatty acids, has been implicated in metabolic syndrome. However, the effect of GPR120 on intestinal homeostasis is still unknown. Here, we showed that deficiency of GPR120 resulted in more severe colitis in mice induced by dextran sodium sulfate (DSS) and Citrobacter Rodentium. Interestingly, CD4+ T cells expressed a high level of GPR120, and mice specifically lacking GPR120 in CD4+ T cells were more susceptible to DSS-induced colitis. Besides, GPR120-deficient CD45Rbhi CD4+ cells are more colitogenic in Rag-/- mice, in which IL-17 and IFNg producing CD4+ T cells were increased but IL-10 production by CD4+ T cells was reduced. Furthermore, CpdA, the GPR120 agonist, promoted CD4+ T effector cell production of IL-10 through upregulating Blimp1 and inducing glycolysis, which were regulated by mTOR pathway. Besides, docosahexaenoic acid, a dietary long-chain fatty acid, also upregulated the IL-10 production in CD4+ T cells. Additionally, GPR120 agonist-treated Th1 effector cells induced less severe colitis, whereas this protection was absent in Blimp1-deficient Th1 cells. Importantly, oral administration of CpdA protected mice against intestinal inflammation. Thus, our findings demonstrate the roles of dietary fatty acids receptor GPR120 in regulating intestinal CD4+ T cell production of IL-10 and intestinal homeostasis.
The intestines harbor over trillions of commensal bacteria, which co-evolve and form a mutualistic relationship with the host, with microbial-host interaction shaping immune adaption and bacterial communities. The intestinal microbiota not only benefits the host and contributes to the maintenance of intestinal homeostasis, but also causes chronic intestinal inflammation under certain conditions. Thus, understanding the microbiota regulation of inflammatory bowel disease (IBD) will provide great insights into the pathogenesis of IBD as well as potential therapeutics for IBD patients.
The present paper, by using interspecific chimera of chick and quail and submicroscopic study on the bursal follicle associated epithelium (FAE) cells during differentiation, indicates that FAE cells of the bursa of Fabricius are formed not by differentiation of the epithelial cells but originate from the mesenchymal cells after invading the bursal anlage, and then differentiate into FAE cells. A new suggestion is given on the interpretation of the mechanism of the invasion of hemopoietic stem cells into the bursal epithelium.
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