Immune-mediated autoimmune and inflammatory diseases are a major public health issue. Defining the regulatory mechanisms that normally function to prevent pulmonary inflammation is therefore a key to understanding the etiology of these diseases, and for developing therapeutic strategies to boost these activities in patients. Regulatory T cells (TR) expressing the transcription factor Foxp3 play a critical role in preventing autoimmunity and limiting immune-mediated inflammation. We have shown that during type-1 inflammatory responses, Foxp3+ TR upregulate the Th1-specifying transcription factor Tbx21 (T-bet), and that T-bet expression is critical for proper TR homeostasis and function during Th1-mediated inflammation. Therefore, the goals of this proposal are to determine in detail how loss of T-bet specifically within Foxp3+ TR impacts the initiation, progression and termination of Th1 responses in vivo (Specific Aim 1);analyze at the molecular level how Foxp3 and T-bet combine to control the expression of genes involved in Th1/TR differentiation, homeostasis and function (Specific Aim 2);and to identify the cytokines and cellular signals that control the phenotypic and functional differentiation of different TR subsets (Specific Aim 3).

Public Health Relevance

Understanding how regulatory T cells modulate Th1- and Th17mediated immune responses has clear and direct implications in the clinical application of these cells for the treatment of immune-mediated inflammatory and autoimmune diseases caused by dysregulated Th1 cell responses, such as granulomatous inflammation associated with persistent Mycobacterium tuberculosis infection, hypersensitivity pneumonitis, psoriasis, rheumatoid arthritis, type-1 diabetes and multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI085130-01A1
Application #
7988194
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
1
Fiscal Year
2010
Total Cost
$451,800
Indirect Cost
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
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