The overarching goals of this project are to elucidate the roles of TCR??? pairing and thymic selection in creating the T cell repertoire specific for foreign antigens, and to identify how failures in this process lead to Type-1 Diabetes. We have identified TCRs with a variety of peptide-MHC (pMHC) reactivity patterns, some of which are self-tolerant and pMHC specific while others are overtly self-reactive and pMHC cross-reactive. Our preliminary studies show that this spectrum of TCR reactivity patterns occurs because particular TCR V gene residues can bind pMHC using a variety of different binding modes. The first set of experiments of this proposal will uncover how TCRs are created with different pMHC binding modes, and determine if a subset of pMHC binding modes are intrinsically self-reactive. The second set of experiments in this proposal will test the model that central tolerance functions to limit mature T cells from expressing TCRs with an enhanced pMHC cross-reactive phenotype, and that self-reactive T cells that also have enhanced pMHC cross-reactivity are the subset of lymphocytes which trigger the autoimmune cascade leading to Type-1 Diabetes. We will determine whether defects in negative selection in autoimmune susceptible NOD mice allow a subset of self-reactive T cells to develop that express TCRs with enhanced pMHC cross-reactivity. We predict cross-reactive T cells are the most difficult T cell subset to control throuh peripheral tolerance mechanism, and it is these T cells which become activated and trigger the autoimmune cascade causing T1D. These experiments proposal will identify molecular mechanisms that control the specificity of TCRs, and identify how defects in immune regulation allow self-reactive T cells to trigger Type 1 Diabetes.

Public Health Relevance

All individuals carry T cells in their mature T cell repertoire which can react with self-tissues, yet only some individuals succumb to autoimmunity. Why particular self-reactive T cells become activated and trigger autoimmune disease, while others stay quiescent is unknown. The experiments of this proposal will uncover why self-reactive T cells are created and identify how defects in immune regulation allow self-reactive T cells to trigger Type 1 Diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095077-03
Application #
8639567
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Spain, Lisa M
Project Start
2012-04-15
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$357,788
Indirect Cost
$140,288
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Sasaki, Katsuhiro; Bean, Angela; Shah, Shivanee et al. (2014) Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells. J Immunol 192:3029-42
Stadinski, Brian D; Huseby, Eric S (2014) Identifying environmental antigens that activate myelin-specific T cells. Trends Immunol 35:231-2
Keck, Simone; Schmaler, Mathias; Ganter, Stefan et al. (2014) Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation. Proc Natl Acad Sci U S A 111:14852-7
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