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 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 #
5R01AI085130-05
Application #
8662166
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
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$427,507
Indirect Cost
$138,427
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Smigiel, Kate S; Richards, Elizabeth; Srivastava, Shivani et al. (2014) CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 211:121-36
Srivastava, Shivani; Koch, Meghan A; Pepper, Marion et al. (2014) Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med 211:961-74
Srivastava, Shivani; Koch, Lisa K; Campbell, Daniel J (2014) IFN?R signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease. J Immunol 193:2733-42
Smigiel, Kate S; Srivastava, Shivani; Stolley, J Michael et al. (2014) Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol Rev 259:40-59
Shafiani, Shahin; Dinh, Crystal; Ertelt, James M et al. (2013) Pathogen-specific Treg cells expand early during mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12. Immunity 38:1261-70
Campbell, Daniel J; Koch, Meghan A (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11:119-30