Immune-mediated diseases of the colon such as inflammatory bowel disease may be related to a loss of tolerance to commensal bacteria. We have found that in the normal setting, colonic tolerance appears to be maintained via the recognition of commensal bacteria by inducible regulatory T (iTreg) cells. Based on our studies of the colonic TCR repertoire, we have generated two novel transgenic lines expressing bacteria- specific iTreg TCRs. This will allow us to directly assess bacteria-specific iTreg versus effector T cell differentiation under various experimental conditions.
In Aim 1, we will manipulate the bacterial population and determine their impact on iTreg cell generation using the TCR transgenic lines, as well as on a polyclonal CD4+ T cell population using TCR repertoire analysis.
In Aim 2, we will investigate the antigen-presenting cells and signals that are involved in T cell recognition of bacteria and differentiation into iTreg, rather than effector, cells. Finaly, in Aim 3, we will move beyond normal physiology and study the effect of infections as well as genetic mutations associated with IBD on iTreg cell development, addressing the hypothesis that CD4+ T cell tolerance is broken during immune mediated colitis. We believe that understanding the mechanisms which regulate the development and stability of bacteria-specific colonic iTreg cells will be useful for facilitating the development of Treg cell-mediated therapy fr IBD.

Public Health Relevance

Inflammatory bowel disease (IBD) afflicts approximately 0.1 - 0.2% of the general population, and causes significant morbidity and mortality from abdominal pain, weight loss, diarrhea, bleeding, and cancer. Current research suggests that genetic predisposition results in abnormal responses to commensal bacteria, and may result from a loss of T cell-mediated immune regulation to commensal bacteria. Thus, the goal of this proposal is to understand the mechanisms of T cell tolerance in the colon to potentially facilitate the development of novel therapies for IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094995-02
Application #
8625745
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2013-02-25
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$297,540
Indirect Cost
$101,790
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ai, Teresa L; Solomon, Benjamin D; Hsieh, Chyi-Song (2014) T-cell selection and intestinal homeostasis. Immunol Rev 259:60-74
Chai, Jiani N; Zhou, You W; Hsieh, Chyi-Song (2014) T cells and intestinal commensal bacteria--ignorance, rejection, and acceptance. FEBS Lett 588:4167-75