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

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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 (M1))
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University of Minnesota Twin Cities
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Hogquist, Kristin A; Jameson, Stephen C (2014) The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function. Nat Immunol 15:815-23
Klein, Ludger; Kyewski, Bruno; Allen, Paul M et al. (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14:377-91
Dunmire, Samantha K; Odumade, Oludare A; Porter, Jean L et al. (2014) Primary EBV infection induces an expression profile distinct from other viruses but similar to hemophagocytic syndromes. PLoS One 9:e85422
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Pauken, Kristen E; Linehan, Jonathan L; Spanier, Justin A et al. (2013) Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice. J Immunol 191:4913-7
Stritesky, Gretta L; Xing, Yan; Erickson, Jami R et al. (2013) Murine thymic selection quantified using a unique method to capture deleted T cells. Proc Natl Acad Sci U S A 110:4679-84
Gerner, Michael Y; Heltemes-Harris, Lynn M; Fife, Brian T et al. (2013) Cutting edge: IL-12 and type I IFN differentially program CD8 T cells for programmed death 1 re-expression levels and tumor control. J Immunol 191:1011-5
Martinez, Ryan J; Zhang, Na; Thomas, Stephanie R et al. (2012) Arthritogenic self-reactive CD4+ T cells acquire an FR4hiCD73hi anergic state in the presence of Foxp3+ regulatory T cells. J Immunol 188:170-81
Mueller, Daniel L (2010) Mechanisms maintaining peripheral tolerance. Nat Immunol 11:21-7
Curtsinger, Julie M; Mescher, Matthew F (2010) Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 22:333-40

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