Suppressor or regulatory T cells (Tregs) play a key role in maintaining T cell homeostasis and preventing autoimmunity. However, the molecular mechanisms that regulate their development and survival remain poorly characterized. Several studies have demonstrated that signals initiated by the IL2 receptor (IL2R) are required for both Treg development and homeostasis; however, we lack information on the downstream pathways that entrain these processes. Specifically, the IL2R has been shown to lead to the activation of at least three major signaling pathways involving the small G protein Ras, the lipid kinase PI3K, and the related transcription factors, STAT5a and STAT5b. Our hypothesis is that the IL2R primarily promotes Treg development and homeostasis via activation of the transcription factor STATS. Supporting this assertion, we have generated transgenic mice that express a constitutively active form of STAT5b (called STAT5b-CA), and which exhibit a dramatic increase in the number of CD4+CD25+ T cells that possess regulatory T cell activity. Thus, the aims of this grant are to (i) ascertain how the IL2R induces Treg development, survival, and function, with a focus on STAT5 signaling, and (ii) to characterize the molecular mechanisms by which STAT5 promotes Treg development. These studies will illuminate the process by which STAT5 directs regulatory T cell development and homeostasis. Furthermore, they should provide insights into molecular mechanisms that will allow for the manipulation of Treg numbers and function and thereby prove useful for designing novel approaches aimed at preventing or suppressing autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061165-02
Application #
7007657
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Rothermel, Annette L
Project Start
2005-02-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
2
Fiscal Year
2006
Total Cost
$314,201
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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