The objective of this study is to determine how specific combinations of homing receptors control the localization and function of CD4+CD25+ regulatory T cells (Treg). As potent modulators of self-reactive T cells, Treg represent an exciting new therapeutic approach for the treatment of autoimmune disorders such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and Chron's disease. However, as a prerequisite to understanding how Treg function in vivo to control autoimmunity, it is essential to determine where Treg localize and what cell types they interact with. While Treg express diverse and heterogeneous patterns of lymphocyte homing receptors, the relationship between their homing receptor expression, their localization, and their ability to modulate organ-specific autoimmunity has not been explored experimentally. We hypothesize that Treg must localize to and function within specific lymphoid and non-lymphoid tissues in order to prevent autoimmunity;Here we propose a series of experiments to test this hypothesis, and determine how disrupting Treg localization impacts their functional ability to prevent systemic and organ-specific autoimmunity (aim 1) and their survival/homeostasis (aim 2). In addition, we will test the hypothesis that homing receptor expression defines Treg subsets targeted to lymphoid vs. non-lymphoid tissues that have distinct functional and homeostatic characteristics (aim 3). Determining the relationship between Treg homing and their ability to control autoimmunity is required to understand where these cells function in vivo, and how diverse populations of Treg may function at distinct sites to prevent the initiation and/or progression of autoimmunity. This has clear and direct implications in the clinical application of Treg to the prevention and treatment of human autoimmune and inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067750-04
Application #
7613421
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
2006-05-15
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$435,793
Indirect Cost
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Stolley, J Michael; Campbell, Daniel J (2016) A 33D1+ Dendritic Cell/Autoreactive CD4+ T Cell Circuit Maintains IL-2-Dependent Regulatory T Cells in the Spleen. J Immunol 197:2635-45
Campbell, Daniel J (2015) Control of Regulatory T Cell Migration, Function, and Homeostasis. J Immunol 195:2507-13
Buechler, Matthew B; Gessay, Griffin M; Srivastava, Shivani et al. (2015) Hematopoietic and nonhematopoietic cells promote Type I interferon- and TLR7-dependent monocytosis during low-dose LCMV infection. Eur J Immunol 45:3064-72
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Duhen, Thomas; Campbell, Daniel J (2014) IL-1? promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol 193:120-9
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
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
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Duhen, Thomas; Duhen, Rebekka; Lanzavecchia, Antonio et al. (2012) Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119:4430-40

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