Chronic inflammatory diseases of the gut, such as inflammatory bowel disease, are often potentiated by the same microbial species that colonize healthy individuals, such as the Helicobacter species. It has been unclear how the pro-inflammatory effector T cell response to these so-called pathobionts is restrained during normal gut homeostasis. Now, Littman and collegues describe a population of pathobiont-specific peripherally derived regulatory T (pTreg) cells that selectively restrain pathobiont-driven inflammation in healthy mice.

Credit: Macmillan Publishers Limited

Helicobacter hepaticus stably colonizes the large intestine of wild-type mice but causes T helper 17 (TH17) cell-mediated inflammation in mice with a deficiency of IL-10-mediated immune tolerance. Using this model, the authors cloned H. hepaticus-specific T cell receptor (TCR) sequences from the inflammatory TH17 cells and identified immunodominant peptide epitopes of H. hepaticus. Using mice transgenic for one of the cloned TCRs (for example, HH7-2tg mice) or MHC class II tetramers loaded with H. hepaticus peptide, they could track H. hepaticus-specific T cells in vivo. When naive HH7-2tg T cells were transferred into wild-type mice colonized with H. hepaticus, they accumulated in the large intestinal lamina propria and differentiated mainly into forkhead box protein P3 (FOXP3)+ pTreg cells. By contrast, when HH7-2tg T cells were transferred into colonized IL-10-deficient mice, they mainly differentiated into TH17 cells with pro-inflammatory TH1 cell-like features. Similar differentiation profiles were observed for the adoptive transfer of other H. hepaticus-specific T cell clones.

MAF is a crucial cell-intrinsic factor for the differentiation of H. hepaticus-specific pTreg cells

The transcription factor MAF was shown to be highly enriched in the HH7-2tg pTreg cells. In H. hepaticus-colonized mice with a conditional deletion of Maf in FOXP3+ cells, the proportion of Treg cells in the large intestine was markedly decreased, with a concomitant increase in the number of TH17 cells. Furthermore, H. hepaticus-specific T cells were mainly TH17 cells rather than Treg cells in the mice with conditional Maf deletion in Treg cells. Most of these TH17 cells expressed MAF, which indicates that they do not arise from the MAF-deficient Treg cells. Thus, the results suggest that MAF is a crucial cell-intrinsic factor for the differentiation of H. hepaticus-specific pTreg cells that control a separate population of H. hepaticus-specific TH17 cells. MAF-deficient pTreg cells were also functionally impaired in terms of defective expression of IL-10 and Treg cell signature genes.

In support of a role for MAF-expressing Treg cells in controlling spontaneous inflammatory responses to pathobionts, H. hepaticus-colonized mice with conditional deletion of MAF in Treg cells had signs of spontaneous colitis. Similar results were observed for mice with impaired signal transducer and activator of transcription 3 (STAT3) or transforming growth factor-β signalling in Treg cells, both of which are required for MAF expression. Finally, the authors showed that H. hepaticus-specific Treg cells were better at suppressing colitis than polyclonal Treg cells in an adoptive transfer model, which highlights an important role for pathobiont-specific pTreg cells in addition to thymus-derived 'natural' Treg cells in maintaining gut homeostasis.