Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet ( cells. Studies of the nonobese diabetic (NOD) mouse model of the disease indicate that CD8+ T cells are required for T1D development. We used ( cell-cytotoxic CD8+ T cell clones isolated from NOD mice to identify two antigenic targets for early insulitic T cells. These are islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and dystrophia myotonica kinase (DMK). Considered together with the third known target of early insulitic CD8+ T cells (i.e., insulin), these three specificities can collectively account for up to half of the islet-infiltrating CD8+ T cells in NOD mice. Here we will translate our findings to human T1D by using islet-infiltrating T cells from HLA-transgenic NOD mice to map the epitopes of these ( cell antigens that are targeted by HLA-A*0201-restricted T cells. The hypothesis that HLA-A*0201 -positive patients and HLA-transgenic mice will exhibit overlapping specificities with respect to the epitopes they recognize will then be evaluated. Next, our newly developed ability to deliver ( cell antigens to steady-state dendritic cells (DCs) via the endocytic receptor DEC-205 will permit us to test the hypothesis that this treatment will result in CD8+ T cell tolerance and improvement of disease. We will examine the impact of DC targeting of an IGRP-derived peptide on both transferred and endogenous IGRP-reactive CD8+ T cells, utilizing approaches that will enable us to monitor IGRP-specific T cells in terms of both number and function, including a cytotoxicity assay that we have devised to permit detection of IGRP-specific T cell cytotoxicity in vivo. IGRP has been chosen for these studies, because it is a CD8+ T cell antigen of major importance in NOD mice. Finally, a """"""""high-throughput"""""""" approach to antigen discovery will be employed to permit a more complete characterization of the antigens targeted by CD8+ T cells in the NOD mouse model, which will increase its utility in optimizing therapies and exploring the immunopathogenesis of T1D. Retroviral transduction of bone marrow stem cells will be used to rapidly generate NOD mice expressing T cell receptors from early insulitic ( cell-cytotoxic CD8+ T cell clones of unknown specificity. These mice will be used as a T cell source for antigen discovery. In summary, our work will facilitate the development of strategies to interfere with pathogenic T cell populations, as well as assays to monitor autoimmune activity. ? Relevance in lay language: ( cells in the pancreas make insulin, which is essential for controlling how sugar is used in the body. Type 1 diabetes occurs when the immune system kills the ( cells and insulin can no longer be made. The proposed work will identify the molecular targets of the destructive immune cells and develop methods to monitor and control their activity. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064315-06
Application #
7491143
Study Section
Special Emphasis Panel (ZRG1-HAI-G (09))
Program Officer
Spain, Lisa M
Project Start
2003-04-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
6
Fiscal Year
2008
Total Cost
$307,953
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Schloss, Jennifer; Ali, Riyasat; Racine, Jeremy J et al. (2018) HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression. J Immunol 200:3353-3363
Racine, Jeremy J; Stewart, Isabel; Ratiu, Jeremy et al. (2018) Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development. Diabetes 67:923-935
Sidney, John; Schloss, Jennifer; Moore, Carrie et al. (2016) Characterization of the peptide binding specificity of the HLA class I alleles B*38:01 and B*39:06. Immunogenetics 68:231-6
Babad, Jeffrey; Ali, Riyasat; Schloss, Jennifer et al. (2016) An HLA-Transgenic Mouse Model of Type 1 Diabetes That Incorporates the Reduced but Not Abolished Thymic Insulin Expression Seen in Patients. J Diabetes Res 2016:7959060
Ali, Riyasat; Babad, Jeffrey; Follenzi, Antonia et al. (2016) Genetically modified human CD4(+) T cells can be evaluated in vivo without lethal graft-versus-host disease. Immunology 148:339-51
Babad, J; Mukherjee, G; Follenzi, A et al. (2015) Generation of ? cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice. Clin Exp Immunol 179:398-413
Mukherjee, Gayatri; Chaparro, Rodolfo J; Schloss, Jennifer et al. (2015) Glucagon-reactive islet-infiltrating CD8 T cells in NOD mice. Immunology 144:631-40
Lamont, Deanna; Mukherjee, Gayatri; Kumar, P Rajesh et al. (2014) Compensatory mechanisms allow undersized anchor-deficient class I MHC ligands to mediate pathogenic autoreactive T cell responses. J Immunol 193:2135-46
Mukherjee, Gayatri; Geliebter, Ari; Babad, Jeffrey et al. (2013) DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8? T cells independently of PD-1 and PD-L1. Int Immunol 25:651-60
Antal, Zoltan; Baker, Jason C; Smith, Carla et al. (2012) Beyond HLA-A*0201: new HLA-transgenic nonobese diabetic mouse models of type 1 diabetes identify the insulin C-peptide as a rich source of CD8+ T cell epitopes. J Immunol 188:5766-75

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