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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Spain, Lisa M
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Rowe, Jared H; Stadinski, Brian D; Henderson, Lauren A et al. (2017) Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity. J Allergy Clin Immunol 140:1739-1743.e7
Stadinski, Brian D; Shekhar, Karthik; Gómez-Touriño, Iria et al. (2016) Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat Immunol 17:946-55
Wyss, Lena; Stadinski, Brian D; King, Carolyn G et al. (2016) Affinity for self antigen selects Treg cells with distinct functional properties. Nat Immunol 17:1093-101
Stadinski, Brian D; Obst, Reinhard; Huseby, Eric S (2016) A ""hotspot"" for autoimmune T cells in type 1 diabetes. J Clin Invest 126:2040-2
Attaf, Meriem; Huseby, Eric; Sewell, Andrew K (2015) ?? T cell receptors as predictors of health and disease. Cell Mol Immunol 12:391-9
Huseby, Eric S; Kamimura, Daisuke; Arima, Yasunobu et al. (2015) Role of T cell-glial cell interactions in creating and amplifying central nervous system inflammation and multiple sclerosis disease symptoms. Front Cell Neurosci 9:295
Parello, Caitlin S; Huseby, Eric S (2015) Indoctrinating T cells to attack pathogens through homeschooling. Trends Immunol 36:337-43
Stadinski, Brian D; Trenh, Peter; Duke, Brian et al. (2014) Effect of CDR3 sequences and distal V gene residues in regulating TCR-MHC contacts and ligand specificity. J Immunol 192:6071-82
Stepanek, Ondrej; Prabhakar, Arvind S; Osswald, Celine et al. (2014) Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell 159:333-45
Stadinski, Brian D; Huseby, Eric S (2014) Identifying environmental antigens that activate myelin-specific T cells. Trends Immunol 35:231-2

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