Over millions of years, microbes that have colonized and coevolved with humans have gradually come to help regulate nutrition and metabolism processes and train both innate and adaptive immune responses. Among commensal microorganisms that colonize healthy individuals, pathobionts -including Helicobacter species- are those that can potentially induce chronic inflammatory responses in genetically susceptible hosts or in the presence of certain exogenous stimuli including antibiotic treatments and stress. However, little is known regarding immune mechanisms involved in shifting commensal microbes to a pathogenic profile.
A new study, led by Prof. Dan R. Littman from the Kimmel Centre for Biology and Medicine of the Skirball Institute and The Howard Hughes Medical Institute at New York University School of Medicine (New York), has found that induced regulatory T (Treg) cells in the gut are critical for immune tolerance to gut pathobionts through the transcription factor c-MAF.
The researchers first found that Helicobacter hepaticus predominantly induced inflammatory T helper 17 (Th17) cells in mouse models of interleukin(IL)-10 deficient-dependent colitis and Citrobacter rodentium-induced colonic inflammation. H. hepaticus-specific skewing from regulatory T cells to Th17 cells indicate that dysregulated T cell tolerance to pathobionts could contribute to the development of inflammatory bowel diseases such as ulcerative colitis.
However, colonization of wild-type mice by H. hepaticus promoted the differentiation of RORgt+FOXP3+ regulatory T (iTreg) cells that selectively restrain pro-inflammatory Th17 cells and whose function was dependent on the transcription factor c-MAF. Thus, RORgt+ iTreg cells are required for immune tolerance to gut pathobionts and to maintain gut homeostasis via the transcription factor c-MAF, which was enriched in these cells and has been previously shown to be involved in an anti-inflammatory profile in other T helper cell subsets.
Inactivation of c-MAF in the Treg cell compartment resulted in the accumulation of H. hepaticus-specific inflammatory Th17 cells and spontaneous colitis, together with impaired IL-10 production and differentiation of bacteria-specific iTreg cells. Besides this, RORgt inactivation in Treg cells did not significantly affect the bacteria-specific Treg and Th17 cell balance. These data indicate that c-MAF is required for the differentiation and function of induced Treg cells in the gut. According to the authors, these results suggest that pathobiont-dependent inflammatory colitis is driven by gut microbiota-reactive T cells that have escaped the c-MAF-dependent mechanism of iTreg-Th17 homeostasis.
In conclusion, this study shows a new mechanism by which the immune system prevents potentially useful bacteria from causing gut inflammatory responses. Thus, pathobiont-driven inflammatory bowel diseases may rely on T cells that have escaped the normal tolerance system of the host, which may lead to attack by commensal species that usually are not involved in disease.
According to Prof. Littman in a press release: “If confirmed, future treatments may consist of groups of bacterial species, or key pieces of them, chosen because they can turn on sets of Tregs to quiet overall gut inflammation.”
Xu M, Pokrovskii M, Ding Y, et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature. 2018; 554(7692):373-7. doi: 10.1038/nature25500.