Tu174 - Peripheral Regulatory T-Cells Specific for Commensal Bacterial Flagellins Control Th17-Mediated Inflammation and Polyposis

Shirin Eyvazi Khasraghi – Postdoctoral Fellow, Mayo Clinic; Mohsen Khosravi Maharlooei – Mayo Clinic; Abu Osman, PhD – Mayo Clinic; Fotini Gounari – Mayo Clinic; Charles Elson – University of Alabama; Khashayarsha Khazaie – Dept of Immunology – Mayo Clinic

Abstract Text: RORgt+ regulatory T-cells (Tregs) express high levels of IL10 and control microbial-instigated T-helper 17 (Th17) inflammation. In inflammatory bowel diseases and colorectal cancer (CRC), loss of the anti-inflammatory properties of Tregs contributes to deregulated inflammation and escalation of pathogenic Th17 responses. We have established that increased numbers of specific pathobionts (such as Parvimonias Micra) lead to increased polyp loads in the small bowel and colon of CRC-prone mice, as well as changes in the epigenome and gene expression in host cells, and long-term changes in microbiome composition. Conversely, RORgt+ Tregs generated in a microbial specific manner by protective bacterial strains (such as those from the Lachnospiraceae family) may be highly resilient in controlling inflammation and have therapeutic potential. The Lachnospiraceae flagellin CBir has been established in mouse models as an important antigen in the immune response for inflammatory bowel diseases (such as Crohn’s), where it generates specific, protective RORgt+ Tregs. Our exploration is focused on the impact of CBir-specific Tregs, their distribution, stability, and influence on polyposis in colorectal cancer.
Mice colonized with Lachnospiraceae A4 were injected with naïve CD4+ CBir TCR transgenic T-cells. These cells were allowed to proliferate for 4 days in the mice. Flow cytometry of extracted mesenteric lymph nodes, small bowel, colon, and spleen aim to detect proliferation of donor CD4+ T-cells and conversion into Tregs. Ongoing analyses determine the impact of polyposis on activation of CBir TCR specific Tregs, CBir TCR Treg suppression of inflammation and polyposis, and Treg stability in the course of disease.