The major histocompatibility complex (MHC) class II locus is strongly associated with the risk of type 1 diabetes, and tissue specificity of the autoimmunity causing diabetes is likely to be determined by the trimolecular complex composed of an MHC molecule, an antigen, and a T cell receptor (TCR). We hypothesize that the interactions between components of this trimolecular complex, all of which are encoded in the germline, determines the nature of T cells involved in the development of type 1 diabetes. Targeting of an insulin B chain 9-23 amino acid peptide (insulin B:9-23) is highly likely to be an essential determinant in the initiation of islet inflammation in the spontaneous diabetes animal model, NOD mouse. We recently discovered that TCRs containing the germline-encoded variable gene (Vgene) sequence called TRAV5D-4 play a critical role to induce anti-islet autoimmunity via the recognition of insulin B:9-23 peptide. Thus, the trimolecular complex consisting of the insulin B:9-23 peptide and TRAV5D-4 TCR alpha chain plays a key role in developing anti-islet autoimmunity; however, how T cells expressing TRAV5D-4 TCRs contribute to the initiation and development of the disease remains to be elucidated. Given evidence that the DQ8 diabetes- susceptible HLA class II molecule is an ortholog of NOD I-Ag7 presenting the insulin B:9-23 peptide and that T cells expressing TRAV13-1 (human ortholog of TRAV5D-4) TCR alpha chains dominantly exist in the pancreas of a type 1 diabetes patient having DQ8, the ultimate goal of this proposal is to verify a proof of concept that insulin targetig by a specific germline-encoded TCR Vgene motif plays a critical role in the development of islet autoimmunity. In this proposal, we aim to determine the molecular mechanism of how TCRs, in particular those containing TRAV5D-4, target the critical peptide, insulin B:9-23, to initiate isle inflammation using the NOD mouse model (Aim 1), and to determine whether T cells expressing TRAV5D-4 are essential for diabetes development in NOD mice (Aim 2). If the development of anti-islet autoimmunity is completely suppressed in the absence of TRAV5D-4, targeting only T cells expressing such essential TRAV genes will enable us to develop a robust immunotherapy with the minimum of side effects. Finally, we will pursue the hypothesis that there is a conceptually similar interaction in the human trimolecular complex consisted of the insulin B:9-23 peptide and TRAV13-1 TCR Vgene motif underlying susceptibility to human type 1 diabetes (Aim 3). Findings from this proposal will provide a deeper understanding of the principles underlying the initiation of islet autoimmunity via the interaction within the insulin trimolecular complex, which will ultimately to be applied to design antigen-based immunodiagnostic and immunotherapeutic clinical studies for type 1diabetes in humans.

Public Health Relevance

The proposed research will enhance our understanding of the mechanism how our own tissues are destroyed by the immune system and ultimately why autoimmune diseases occur. The knowledge gained by this proposal will lead us to develop therapies to prevent and cure autoimmune diseases such as 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 #
4R01DK099317-04
Application #
9104151
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2013-08-20
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Burrack, Adam L; Landry, Laurie G; Siebert, Janet et al. (2018) Simultaneous Recognition of Allogeneic MHC and Cognate Autoantigen by Autoreactive T Cells in Transplant Rejection. J Immunol 200:1504-1512
Michels, Aaron W; Landry, Laurie G; McDaniel, Kristen A et al. (2017) Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes. Diabetes 66:722-734
Marrack, Philippa; Krovi, Sai Harsha; Silberman, Daniel et al. (2017) The somatically generated portion of T cell receptor CDR3? contributes to the MHC allele specificity of the T cell receptor. Elife 6:
Seay, Howard R; Yusko, Erik; Rothweiler, Stephanie J et al. (2016) Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. JCI Insight 1:e88242
Nakayama, Maki; Simmons, Kimberly M; Michels, Aaron W (2015) Molecular Interactions Governing Autoantigen Presentation in Type 1 Diabetes. Curr Diab Rep 15:113
Nakayama, Maki; McDaniel, Kristen; Fitzgerald-Miller, Lisa et al. (2015) Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects. Proc Natl Acad Sci U S A 112:4429-34
Zhang, Li; Crawford, Frances; Yu, Liping et al. (2014) Monoclonal antibody blocking the recognition of an insulin peptide-MHC complex modulates type 1 diabetes. Proc Natl Acad Sci U S A 111:2656-61
Bettini, Maria; Blanchfield, Lori; Castellaw, Ashley et al. (2014) TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential. J Immunol 193:571-9
Bettini, Matthew L; Bettini, Maria; Nakayama, Maki et al. (2013) Generation of T cell receptor-retrogenic mice: improved retroviral-mediated stem cell gene transfer. Nat Protoc 8:1837-40

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