Advisory Committee Chair
Craig L Maynard
Advisory Committee Members
Laurie E Harrington
Andre Ballesteros-Tato
Charles O Elson III
John F Kearney
Document Type
Dissertation
Date of Award
2021
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Genome wide association studies (GWAS) have identified a loss-of-function mutation in the gene encoding inducible T cell costimulator ligand (ICOSL) as correlating with inflammatory bowel disease (IBD). The reason for this association was largely unknown. ICOS signals have been implicated in controlling the dynamics of regulatory T (Treg) cells, which are essential to intestinal homeostasis. Compared to WT mice, ICOS-deficient mice possessed fewer Treg cells in the colonic lamina propria (cLP). The deficit in ICOS-deficient Treg cell numbers was attributable to preferential loss of Foxp3 expression. Bisulfite sequencing revealed that ICOS-deficient Treg cells did not demethylate conserved noncoding sequence 2 (CNS2) of Foxp3, an epigenetic change essential to maintaining the Treg cell function. Thus, while Foxp3+ cells from WT mice could prevent and reverse colitis in the CD45RBhi CD4 transfer model, ICOS-deficient Treg cells were incapable of reversing ongoing intestinal inflammation. Our work also investigated the potential of ICOS-ICOSL signals to contribute to antibody-mediated control of intestinal commensals. ICOSL-deficient mice possessed reduced IgA and IgG binding to colonic commensals, including mucus-associated microbial antigens and flagellins. In compensation, ICOSL-deficient mice surprisingly possessed more IL-10 producing CD4 T cells in the cLP than WT. Mice doubly deficient in ICOSL and CD4 T cell derived IL-10 developed spontaneous colitis in early life that could be mitigated through provision of milk from WT dams, which rescued the antibody levels of ICOSL-deficient pups. ICOSL helps protect against colitis throughout life, as adult WT mice remained unaffected while ICOSL-deficient mice exhibited rapid-onset colitis upon temporary depletion of IL-10 producing cells. Our studies have determined ICOS signaling helps stabilize Treg cells to allow suppressive function in the inflamed intestine. We have also found that ICOSL promotes antibody mediated control of commensals and cooperates with IL-10 to quell inflammatory reactions to gastrointestinal microbes. Collectively, our work identifies multiple roles for ICOS-ICOSL signaling in the suppression of intestinal inflammation.
Recommended Citation
Landuyt, Ashley Elizabeth, "Inducible T Cell Costimulator Stabilizes Regulatory T Cell Phenotype And Controls Host-Microbiota Interactions To Reduce Susceptibility To Intestinal Inflammation" (2021). All ETDs from UAB. 835.
https://digitalcommons.library.uab.edu/etd-collection/835