T lymphocytes must respond to specific antigens by rapid proliferation and differentiation to mount an effective immune response. It is critical that this occur only in response to foreign antigen, so that self antigens do not induce autoimmune responses. T cell tolerance to self-antigen is achieved in part by negative selection in the thymus to eliminate clones that recognize self-antigen. This is not complete, however, and some self-reactive T cells escape into the periphery. Mechanisms exist for rendering these mature T cells tolerant to self antigens, but they are poorly understood. This Program is addressing the nature of these mechanisms in mature T cells at the molecular and cellular levels using both in vitro and in vivo models. It is anticipated that the findings obtained in the planned studies will contribute to a better fundamental understanding of how autoimmunity is avoided. In addition, understanding of these mechanisms, and hence the ability to manipulate them, has the potential to contribute to improvements in transplantation and disease therapy. Mechanisms that induce tolerance to self-antigens may also induce tolerance to foreign antigens including those present on tumors or virus-infected cells, resulting in the immune system failing to mount a protective response. Finally, there is great potential for using defined peptide antigens to induce protective or therapeutic immunity for a broad range of diseases and much current effort is focusing on this. However, it is becoming increasingly clear that these must be used with great caution since they can also induce tolerance that may lead to lessened protection or exacerbated disease. Thus, developing a better understanding of the mechanisms that can lead to T cell tolerance, as proposed in this Program, has implications well beyond autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI035296-12
Application #
6763080
Study Section
Special Emphasis Panel (ZAI1-PTM-I (M1))
Program Officer
Nabavi, Nasrin N
Project Start
1997-09-15
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
12
Fiscal Year
2004
Total Cost
$758,631
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
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
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
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

Showing the most recent 10 out of 136 publications