Only T cells with the capacity to bind to self-peptide MHC complexes (self-reactivity) are included in the repertoire because of positive selection. And yet, self-reactivity is also the perilous feature of T cells that cause autoimmune disease. The distinction between useful and dangerous T cells is a matter of degree, with T cells that have a low affinity for self-MHC being useful, and those that have high affinity for self-MHC being dangerous. Yet to date, it has not been possible to study or measure the self-reactivity of diverse polyclonal populations of T cells. We propose to use a novel Nur77GFP BAC transgenic reporter mouse, in combination with tetramer enrichment and various gene deficiency models to quantitative self-reactivity in polyclonal T cells from normal and autoimmune disease prone animals. The three specific aims are: 1) to enumerate and study the T cells that are normally clonally deleted, 2) to define the contribution of CD28, medullary epithelial cells, and dendritic cells to negative selection in the thymus, and 3) to identify and characterize the self-reactive T cells that are present in diabetes-prone mice.

Public Health Relevance

Autoimmune disease is major human health problem whose origins are not well understood, and for which new treatments are strongly needed. This project is relevant because it attempts to identify and study the pool of T lymphocytes that autoimmune disease causing T cells arise from.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI035296-21
Application #
8662148
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Spanier, Justin A; Sahli, Nathanael L; Wilson, Joseph C et al. (2017) Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes. Diabetes 66:3051-3060
Kalekar, Lokesh A; Mueller, Daniel L (2017) Relationship between CD4 Regulatory T Cells and Anergy In Vivo. J Immunol 198:2527-2533
Breed, Elise R; Lee, S Thera; Hogquist, Kristin A (2017) Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. Semin Cell Dev Biol :
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
Schmiel, Shirdi E; Yang, Jessica A; Jenkins, Marc K et al. (2017) Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination. J Immunol 198:623-628
Spanier, Justin A; Frederick, Daniel R; Taylor, Justin J et al. (2016) Efficient generation of monoclonal antibodies against peptide in the context of MHCII using magnetic enrichment. Nat Commun 7:11804
Martinov, Tijana; Spanier, Justin A; Pauken, Kristen E et al. (2016) PD-1 pathway-mediated regulation of islet-specific CD4(+) T cell subsets in autoimmune diabetes. Immunoendocrinology (Houst) 3:
Tubo, Noah J; Fife, Brian T; Pagan, Antonio J et al. (2016) Most microbe-specific naïve CD4? T cells produce memory cells during infection. Science 351:511-4
Pritchard, Gretchen Harms; Cross, Eric W; Strobel, Marjorie et al. (2016) Spontaneous partial loss of the OT-I transgene. Nat Immunol 17:471

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