This program grant consists of four integrated projects: Project 1 (PI Jenkins) Analysis of peripheral tolerance in vivo to identify autoreactive CD4+ T cells from diabetic human patients and diabetic mice using MHC II tetramer reagents, Project 2 (PI Mueller) Functional characterization of anergic T cells. Project 3 (PI Hogquist) to define the self-reactivity of polyclonal populations in health and disease using a novel mouse reporter, and Project 4 (PI Mescher) to investigate the role for CD8+ T cells and critical third signal cytokines during the initiation of type 1 diabetes. Each project requires specific mouse lines and three of the four cores require spontaneous diabetes monitoring, pathological analysis and animal care specifically relevant for diabetes. This analysis will consist of insulitis by standard H&E, and assistance with advanced techniques including immunofluorescence of specific cell types, and flow cytometry from pancreas and pancreatic lymph nodes. This core is ideally suited to conduct these studies because identical techniques and similar analysis have been carried out for >11 years by Dr. Fife (1-8). The principle roles ofthe Autoimmune Mouse Core include: A) Provide cost effective animal care and breeding of NOD, B6.g7 and genetic knockout and transgenic lines on the NOD background for autoimmune experimentation. Development of spontaneous diabetes complicates routine breeding and requires additional attention as well as colony consolidation minimizes redundancy and animal costs. B) Provide diabetes monitoring and diabetes management of core mice. Routine spontaneous diabetes screening and insulin therapy will be provided as necessary for diabetic mouse strains being maintained by the core. Differential genetic knockout or transgenic mice can accelerate diabetes and therefore specialized care may be required. In order to generate sufficient numbers of timed diabetic mice, large cohorts must be maintained and coordinated to provide sufficient and consistent experimental mice. C) Provide diabetes monitoring, treatment, and tissue harvesting of experimental mice. The core will monito

Public Health Relevance

The core will breed autoimmune strains of mice, make experimental animals available to the projects, and provide services for assessment of autoimmune status. This will provide the most cost-effective means of obtaining the experimental mice needed, and will insure uniformity ofthe mice being studied, thus optimizing the comparison and integration of results obtained in the separate projects.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-LAR-I)
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University of Minnesota Twin Cities
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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
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
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

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