c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont


Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases1,2,3,4. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts4,5,6. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγt+FOXP3+ regulatory T (iTreg) cells that selectively restrain pro-inflammatory T helper 17 (TH17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iTreg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic TH17 cells. Inactivation of c-MAF in the Treg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. By contrast, RORγt inactivation in Treg cells had only a minor effect on the bacteria-specific Treg and TH17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iTreg–TH17 homeostasis.

All Authors:
Mo Xu, Maria Pokrovskii, Yi Ding, Ren Yi, Christy Au, Oliver J Harrison, Carolina Galan, Yasmine Belkaid, Richard Bonneau & Dan R Littman

First Authors:
Mo Xu, Maria Pokrovskii

Dan R Littman


       将肝螺杆菌定殖于小鼠肠道中,可促进野生型小鼠中特异的RORγt+FOXP3+调节性T细胞(iTreg)分化,而在IL-10缺陷小鼠中主要诱导促结肠炎的辅助T细胞17(TH17); Treg中转录因子c-MAF失活可损害iTreg的分化和功能(如IL-10的生成),导致肝螺杆菌特异的炎性TH17积聚,促发结肠炎;在肠道菌群诱导的T细胞中,iTreg可约束炎性TH17,使宿主对致病共生菌建立免疫耐受,减少结肠炎,c-MAF对调控肠道内iTreg-TH17的平衡有着至关重要的作用。

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