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.
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.
|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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