Regulatory CD25+CD4 T cells are important mediators of immunologic tolerance and are likely to become a therapeutic target. However, their mechanisms in vivo remain largely unknown, and are the main focus of this proposal. The summary of the preliminary work described here shows that 1) we are able to purify in numbers sufficient for the proposed experiments antigen-specific regulatory CD25+CD4 T cells from wild-type TCR Tg mice and antigen-specific regulatory CD25+CD4 T cells expressing a single known TCR; 2) we have established two complementary in vivo systems to measure suppressive effects of CD25+CD4 T cells on responder T cells in non-lymphopenic animals; 3) we are able to simultaneously visualize the behavior and cellular interactions of antigen-specific CD25+CD4 T cells, antigen-specific responder T cells, and antigen-presenting dendritic cells; 4) CD25+CD4 T cells reduce the size of the T cell population responding to antigen and inhibit production of effector Th1and Th2 cytokines; and 5) CD25+CD4 T cells inhibit homeostatic proliferation of naive T cells in lymphopenic mice. The laboratory is now exceptionally poised to pursue the two specific aims in the proposal. In the first aim we will define the cellular mechanisms of by which CD25+CD4 T cells inhibit the antigen-specific T cell responses within the secondary lymphoid tissues. We will determine the fates of the dendritic cells presenting the antigen as well the antigen-specific CD25+CD4 T cells and responder T cells. In the second aim we will determine how CD25+CD4 T cells shape the development of the T cell compartment during immune reconstitution by homeostatic proliferation. In particular, we will test how CD25+CD4 T cells may regulate potentially auto-aggressive T cell clones under conditions of lymphopenia. Although cellular mechanisms constitute the main focus of this proposal, the experimental systems described are robust and are ideally suited for testing roles of specific molecules in CD25+CD4 T cell-mediated immune regulation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK061961-01A1
Application #
6609957
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Hamilton, Frank A
Project Start
2003-03-01
Project End
2008-02-28
Budget Start
2003-03-01
Budget End
2004-02-28
Support Year
1
Fiscal Year
2003
Total Cost
$326,700
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Winstead, Colleen J; Reilly, Cavan S; Moon, James J et al. (2010) CD4+CD25+Foxp3+ regulatory T cells optimize diversity of the conventional T cell repertoire during reconstitution from lymphopenia. J Immunol 184:4749-60
Winstead, Colleen J; Fraser, Joanne M; Khoruts, Alexander (2008) Regulatory CD4+CD25+Foxp3+ T cells selectively inhibit the spontaneous form of lymphopenia-induced proliferation of naive T cells. J Immunol 180:7305-17
Kang, Johnthomas; Huddleston, Stephen J; Fraser, Joanne M et al. (2008) De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR. J Leukoc Biol 83:1230-9
Fischer, Ursula B; Jacovetty, Erica L; Medeiros, Ricardo B et al. (2007) MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc Natl Acad Sci U S A 104:7181-6
Thorstenson, Kristen M; Herzovi, Laura; Khoruts, Alexander (2005) A model of suppression of the antigen-specific CD4 T cell response by regulatory CD25+CD4 T cells in vivo. Int Immunol 17:335-42
Khoruts, Alexander; Fraser, Joanne M (2005) A causal link between lymphopenia and autoimmunity. Immunol Lett 98:23-31
Khoruts, Alexander; Osness, Richard E; Jenkins, Marc K (2004) IL-1 acts on antigen-presenting cells to enhance the in vivo proliferation of antigen-stimulated naive CD4 T cells via a CD28-dependent mechanism that does not involve increased expression of CD28 ligands. Eur J Immunol 34:1085-90
Hagen, Karin A; Moses, Christina T; Drasler, Erin F et al. (2004) A role for CD28 in lymphopenia-induced proliferation of CD4 T cells. J Immunol 173:3909-15