Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimmunity. Although the thymus appears to be a major site of CD4+CD25+ T cell development, it is still unclear whether there are also peripheral sites of development. We have found recently that CD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in the periphery. Conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells may be a very important mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenance, and a defect in this process could contribute to autoimmune disease development. We have found that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in the thymus, but a significantly lower percentage in the periphery. Furthermore, NOD CD4+CD25- T cells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function, strongly suggesting that NOD mice may have a defect in this conversion process and may, therefore, be unable to maintain this regulatory population. The central hypothesis of this proposal is that enhanced conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells in NOD mice can prevent diabetes. We will test this hypothesis by studying the mechanisms and defects in conversion in NOD mice, determine whether this process can be restored and whether restoration is associated with amelioration of disease. By understanding the defects in conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells in NOD mice, it may be possible to devise strategies to overcome these defects and, thereby, develop therapies to prevent or treat autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064421-02
Application #
7166069
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$358,056
Indirect Cost
Name
University of Louisville
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Gu, Z; Chhabra, A Y; Alard, P et al. (2013) Fc?RI is required for TGF?2-treated macrophage-induced tolerance. Immunobiology 218:1200-6
Tucker, Colleen F; Nebane-Ambe, Doreen L; Chhabra, Anita et al. (2011) Decreased frequencies of CD4+CD25+Foxp3+ cells and the potent CD103+ subset in peripheral lymph nodes correlate with autoimmune disease predisposition in some strains of mice. Autoimmunity 44:453-64