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 #
2P01AI035296-20A1
Application #
8592221
Study Section
Special Emphasis Panel (ZAI1-LAR-I (M1))
Project Start
Project End
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
20
Fiscal Year
2013
Total Cost
$361,037
Indirect Cost
$123,513
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Balfour Jr, Henry H; Odumade, Oludare A; Schmeling, David O et al. (2013) Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 207:80-8
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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