The long-term goal of this project is an understanding of the mechanisms that account for CD4+ T celltolerance to antigens that are presented in the secondary lymphoid organs but not the thymus. Previously, weshowed that naive CD4+ T cells that are exposed to model antigens in the secondary lymphoid organs in theabsence of inflammation proliferate poorly, then most of the progeny die, and the survivors enter an anergicstate characterized by poor lymphokine production. The goal of this application is to establish whether or nota similar series of events accounts for peripheral tolerance to certain natural self-proteins. This has become apressing issue since the discovery that the AIRE transcription factor drives ectopic expression of extrathymicgene products in the thymus. Thus, it remains possible that the physiological role that peripheral tolerancewas thought to play is really played by AIRE-mediated intrathymic tolerance. Here, we will test the hypothesisthat peripheral tolerance is physiologically-relevant by using new tools to identify the tolerance mechanismsthat apply to two pregnancy-specific proteins, one that appears to be regulated by AIRE and another thatdoes not, and one sperm-specific protein. We will determine whether or not these proteins are immunogenicin mice that have never expressed them in the relevant tissue (e.g., non-pregnant female mice), and becomenon-immunogenic in mice after expression (e.g., pregnant female mice). The relevant antigenic peptides willbe identified and used to produce peptide-MHC II multimers. The multimers will then be used with a sensitivenew enrichment method capable of detecting fewer than 100 cells per mouse to enumerate peptide MHC II-specific CD4+ T cells before, during, and after expression of the relevant protein within the polyclonalrepertoires of normal mice. This approach should reveal whether or not the relevant CD4+ T cells are deleted,turn into regulatory cells, or become anergic during or after the period when these developmental^ regulatedself-proteins are expressed. This approach will then be used in gene-targeted mice to determine whether ornot molecules such as Fas and Cbl-b, and others identified by other members of the P01, are involved in theidentified tolerance mechanism. Success would provide the first definitive identification of the peripheraltolerance mechanism that applies to a natural self-antigen. This information should help focus future researchon the relevant mechanism and shed light on the potential ways that it could fail and lead to autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI035296-16
Application #
7673680
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
16
Fiscal Year
2008
Total Cost
$310,872
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Burrack, Adam L; Malhotra, Deepali; Dileepan, Thamotharampillai et al. (2018) Cutting Edge: Allograft Rejection Is Associated with Weak T Cell Responses to Many Different Graft Leukocyte-Derived Peptides. J Immunol 200:477-482
Breed, Elise R; Lee, S Thera; Hogquist, Kristin A (2018) Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. Semin Cell Dev Biol 84:2-10
Osum, Kevin C; Burrack, Adam L; Martinov, Tijana et al. (2018) Interferon-gamma drives programmed death-ligand 1 expression on islet ? cells to limit T cell function during autoimmune diabetes. Sci Rep 8:8295
Ruscher, Roland; Hogquist, Kristin A (2018) Intravenous Labeling and Analysis of the Content of Thymic Perivascular Spaces. Bio Protoc 8:
Kotov, Dmitri I; Kotov, Jessica A; Goldberg, Michael F et al. (2018) Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential. J Immunol 200:2004-2012
Leonard, John D; Gilmore, Dana C; Dileepan, Thamotharampillai et al. (2017) Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen. Immunity 47:107-117.e8
Schuldt, Nathaniel J; Auger, Jennifer L; Spanier, Justin A et al. (2017) Cutting Edge: Dual TCR? Expression Poses an Autoimmune Hazard by Limiting Regulatory T Cell Generation. J Immunol 199:33-38
Kalekar, Lokesh A; Mueller, Daniel L (2017) Relationship between CD4 Regulatory T Cells and Anergy In Vivo. J Immunol 198:2527-2533
Burrack, Adam L; Martinov, Tijana; Fife, Brian T (2017) T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Front Endocrinol (Lausanne) 8:343
Ruscher, Roland; Kummer, Rebecca L; Lee, You Jeong et al. (2017) CD8?? intraepithelial lymphocytes arise from two main thymic precursors. Nat Immunol 18:771-779

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