While exposure to microbial antigens in peripheral sites causes expansion of antigen-specific T cells, a role for antigen-specific expansion had not been identified during T cell development in the thymus. We recently found that intestinal colonization induced intestinal dendritic cells migration to the thymus, driving thymic expansion of microbiota-specific T cells early in life. In contrast, colonization in adulthood leads to expansion of peripheral but not thymic microbiota-specific T cells. Thymic microbiota-specific T cells developed early in life were undifferentiated and caused intestinal inflammation in immunocompromised hosts upon antigen reencounter. We sought to understand regulation of this developmental window and define if thymic expansion of microbiota-specific T cells could be restarted in adult mice. We found that microbiota manipulation reestablished expansion of microbiota-specific T cells in the thymus of adult mice. We are in the process of characterizing these T cells in adulthood to assess their impact on intestinal inflammation. Our data suggests that intestinal colonization controls the generation of thymic microbiota-specific T cells which has the potential to modulate inflammatory processes.
Inflammatory bowel disease (IBD) patients with poorly controlled intestinal inflammation are at an elevated risk for colorectal cancer (CRC). IBD patients exhibit intestinal dysbiosis with expanded proteobacteria such as E. coli. Here, we find that colonization with an E. coli isolated from the intestine of an IBD patient (E. coli 541-15) prevents tumorigenesis in an inflammation-related model of CRC. Colonization increased tumor infiltration of T helper 1 (Th1) cells, cytotoxic T lymphocytes (CTLs), and type 1 innate lymphoid cells (ILC1s) and decreased myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Prevention of tumorigenesis occurs if colonization takes place before induction of inflammation. Intestinal inflammation in colitis models was ameliorated by E. coli 541-15 and this protection depended on IL-10 production by macrophages and IL-10 signaling to the intestinal epithelium. Colonization with E. coli 541-15 also promotes these IL-10 pathways if colonization occurs after tumorigenesis is established. However, this leads to worse CRC outcome, with increased tumor burden alongside decreased tumor infiltration of Th1 cells, CTLs, and ILC1s and increased MDSCs and Tregs. These results identify activation of an IL-10 signaling loop between immune cells and the intestinal epithelium after E. coli colonization that modulates intestinal inflammation and CRC. Importantly, these pathways can be protective or pathogenic depending on timing of activation. Supported by 2021 Ludwig Center Basic and Translational Research Award
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.