Loss of colonic tolerance is a significant clinical problem, as it is thought to result in inflammatory bowel disease. The production of IL-10 by T cells plays an important role in maintaining colonic tolerance. However, it is unclear whether IL-10 is produced by T cells responding to specific antigens potentially derived from bacteria, or is expressed on colonic T cells via non-antigen specific stimuli such as cytokines. The goal of this proposal is to address whether antigen specificity is important in selecting Tr1 and IL-10+ regulatory T (Treg) cells in the colon by sequencing the TRAV14 TCRa repertoire in fixed TCR? transgenic mice. If our hypothesis is correct, we will observe that the IL-10+ subsets utilize a unique set of TCRs, which may be useful for the generation of TCR transgenic models of Tr1 or IL-10+ Treg cell development. Using the TCR sequencing data, we will select common Tr1 and IL-10+ Treg TCRs to determine whether they recognize bacteria, and whether they facilitate thymic or peripheral T cell development. TCRs which reproducibly result in peripheral Tr1 and IL-10+ Treg cell development can then be used to generate TCR transgenic models to study IL-10 regulation in T cells. Thus, these studies will increase our understanding regarding how the IL-10 producing T cell subset is generated, which may be useful for developing novel therapies for human disease.

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. IL-10 is an important molecule required to prevent spontaneous colonic inflammation produced by T cells. The goal of this proposal is to understand how IL-10 expression is induced within T cells, which may lead to the development of novel therapies for IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI097535-02
Application #
8416939
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2012-02-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$228,000
Indirect Cost
$78,000
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