Non-conventional Regulation of Treg Development and Function

IBD is a serious, lifelong illness that is both debilitating and financially costly. There are few effective pharmaceuticals for IBD, and many patients ultimately require surgical treatment. Hence, the development of new therapeutics is an utmost priority. Tregs are vital in maintaining immunological tolerance and preventing inappropriate inflammatory responses. Despite having no obvious functional defects, Tregs are unable to regulate inflammation in human IBD patients. The role of the gut homing molecule CCR9 in IBD is poorly understood. CCR9 is a potential drug target that is currently being investigated due to the potential to disrupt migration of pathogenic T cells to the gut. However clinical trials indicate a protracted therapeutic response. Recent studies have indicated an immunomodulatory role for chemokines in other autoimmune diseases. Metabolism is another factor whose influence on T cell responses is rapidly becoming apparently. Caloric intake, oxygen status, and the presence of specific metabolites all regulate T cell responses. We demonstrate here that CCR9 is preferentially expressed by Teffs and Tregs, and that CCR9 signaling inhibits Tregs. Additionally, CCR9 deficiency is protective in DSS colitis but not adoptive transfer colitis, and depletion of antigen-specific Tregs in a DSS model of colitis restores susceptibility to disease. Lastly, we demonstrate that exogenous glucose can alter T cell responses in a dose-dependent manner both in vitro and in vivo. These findings present new regulatory mechanisms utilized by the intestinal immune system to control CD4+ T cell fate and function. Given further research, these findings may present a new platform for the development of IBD therapeutics.

Name thesis:degree_name

Microbiology and Immunology (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Immunology

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Evans-marin, Heather Leigh

Advisor dc:contributor.advisor

• Cong, Yingzi

Committee members dc:contributor.committeemember

• Pinchuk, Iryna
• Sun, Jiaren
• Milligan, Gregg
• Tan, Xiao-di

• Immunology, T cells, CCR9, metabolism, chemokines, autoimmunity, IBD

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/857

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/857