Study the Treg-IL-27 axis in immune regulation

Regulatory T (Treg) cells, a specialized immune population, are known for their role in maintaining immunological tolerance. Mounting evidence has suggested that Treg cells not only come in “different flavors” phenotypically and functionally and play distinct roles in different tissue microenvironments. Consistent with these findings, our previous analysis of tissue Treg cell transcriptome profiling data has revealed unexpectedly elevated expression of IL-27, specifically in gut-associated Treg cells isolated from inflammatory settings. In humans, genome-wide association studies have identified IL-27 as a candidate gene within a susceptibility locus for inflammatory bowel disorder (IBD). Significantly, less IL-27 was found in people harboring the risk alleles relative to those with the nonrisk alleles. These studies provided evidence linking IL-27 and IBD and suggested that the observed elevations in IL-27 in certain patients probably represent an anti-inflammatory response, albeit insufficient to control the ongoing intestinal inflammation. In this application, by using Treg cell-specific gene targeting approaches, our preliminary results have shown that Treg cell-derived IL-27 is crucial to control Th17 immunity particularly in the intestinal tissue. Further single-cell RNA sequencing (scRNA-seq) analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Nevertheless, the molecular mechanisms and the environment factors that drive the expression of IL-27 specifically in gut Treg cells during inflammation remains poorly defined. Through employing molecular, biochemical, and immunological approaches with whole animal experimentation, we will first examine the Treg cell-intrinsic molecular mechanisms accounted for the induction of IL-27 in intestinal Treg cells particularly under inflammatory conditions. Next, as intestine is a special tissue location colonized by over 100 trillion commensal microorganisms that have been shown to be crucial in modulating Treg cell biology and T cell immunity, by employing cutting-edge microbiome technologies, as well as mice with microbiome interventions, we will identify and functionally validate the potential microbes that contribute to the induction of IL-27 in gut Treg cells. Accomplishing the aims proposed in this application will undoubtedly extend our fundamental knowledge the Treg cell-IL-27 axis in maintaining intestinal homeostasis and provide further insights into tissue specific-Treg cell-mediated immune regulation under different cellular and environmental settings.