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

Abstract

Both microbial and host genetic factors contribute to the pathogenesis of autoimmune disease1–4. Accumulating evidence suggests that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease (IBD), often also colonize healthy individuals. These microbes, including the Helicobacter species, have the propensity to induce pathogenic T cells and are collectively referred to as pathobionts4–6. However, an understanding of how such T cells are constrained in healthy individuals is lacking. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus (H. hepaticus), is mediated by induction of RORγt+Foxp3+ regulatory T cells (iTreg) that selectively restrain pro-inflammatory TH17 cells and whose function is dependent on the transcription factor c-Maf. Whereas H. hepaticus colonization of wild-type mice promoted differentiation of RORγt-expressing microbe-specific iTreg in the large intestine, in disease-susceptible IL-10-deficient animals there was instead expansion of colitogenic TH17 cells. Inactivation of c-Maf in the Treg compartment likewise impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg, resulting in accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. In contrast, RORγt inactivation in Treg only had a minor effect on bacterial-specific Treg-TH17 balance, and did not result in inflammation. Our results suggest that pathobiont-dependent IBD is driven by microbiota-reactive T cells that have escaped this c-Maf-dependent mechanism of iTreg-TH17 homeostasis.

Transcription factor c‐Maf is essential for IL‐10 gene expression in B cells

“…There are extensive reports about the transcriptional regulation of IL‐10 production in myeloid cells and T cells, while few reports are available regarding the regulation of IL‐10 in B cells. The expression of c‐Maf has long been considered as a hallmark of macrophages, Th2 and Th17; however, the precise role of c‐Maf during Breg differentiation was unknown before the present study. Our data demonstrated that c‐Maf could effectively increase the production of IL‐10 + Breg cells.…”

“…Although c‐Maf can transactivate IL‐10 by itself to some extent, robust IL‐10 expression requires interaction with additional transcriptional regulators. In the case of Tr1 cells generated in the presence of IL‐27 or IL‐27/TGF‐ β , c‐Maf cooperates with AhR in the regulation of IL‐10 production in mice as well as humans .…”

Helicobacter hepaticus infection induces chronic hepatitis and fibrosis in male BALB/c mice via the activation of NF‐κB, Stat3, and MAPK signaling pathways

“…For oral infection, H hepaticus was harvested by premoistened sterile cotton swab applicator tip and resuspended in PBS. The concentration of bacterial inoculation dose was determined by the use of a spectrophotometric optical density (OD) analysis at 600 nm and adjusted to OD 600 readings between 1 and 1.5 …”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…ROR γ t + Treg cells specific for Helicobacter hepaticus have also been shown to mediate tolerance to this commensal pathobiont, and a polysaccharide from the same species induces anti‐inflammatory IL‐10 secretion in intestinal macrophages . However, Helicobacter specificity itself does not dictate an anti‐inflammatory programme.…”