Type 1 diabetes is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells and the subsequent inability of the patient to produce the insulin required to properly regulate glucose metabolism. CD8 T cells are important contributors to the demise of beta cells in both the non-obese diabetic (NOD) mouse model of the disease and type 1 diabetes patients. A more complete understanding of the epitopes recognized by these T cells is needed to facilitate the development of antigen- specific strategies to interfere with their pathogenicity, as well as assays to monitor autoimmune activity in at- risk individuals, islet transplant patients, or those undergoing intervention protocols. Our proposed project, though self-contained and modest in scope, addresses these unmet needs.
In Aim 1, we will define the HLA- A2-restricted T cell response to the important autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) using an innovative HLA-A*0201-transgenic NOD mouse model that expresses human IGRP in the absence of its murine counterpart and also lacks murine class I MHC molecules, so all CD8 T cells will be restricted to HLA-A2. We will use the islet-infiltrating CD8 T cells from these newly developed, diabetes-susceptible mice to screen a library consisting of all possible 8-, 9-, 10-, and 11-mer peptides that can be derived from human IGRP. This unbiased strategy will allow us to obtain a comprehensive picture of the spontaneously arising HLA-A2-restricted T cell response to this autoantigen.
In Aim 2, we will characterize these human IGRP epitopes in terms of their MHC binding properties and the pathogenicity of their cognate T cells. Candidate CD8 T cell epitopes from human autoantigens have often been chosen for testing of patient reactivity based on their predicted ability to bind an MHC molecule of interest. However, an emerging view is that the peptides recognized by autoreactive T cells often bind poorly to MHC, allowing escape from immune tolerance mechanisms.
In Aim 1, we will be identifying epitopes of IGRP in a non-biased manner. Thus, we will have the opportunity to examine the HLA-A2-binding ability of the identified epitopes and test the hypothesis that low-affinity binding will be favored. To extend the potential usefulness of our epitopes to patient that are HLA-A2-negative, we will also determine their ability to bind related MHC molecules. Finally, to investigate the pathogenicity of the T cell specificities identified in Aim 1, adoptive transfer of peptide-specific CD8 T cells will be employed. Characterization of the human IGRP epitopes in these ways will allow the identification of those most likely to be useful as therapeutic targets and markers of pathogenic autoimmunity.
The autoimmune disease type 1 diabetes is a growing health problem that is associated with significant morbidity and mortality. The goal of our project is to learn more about the characteristics of the T cells that destroy the insulin-producing beta cells i this disease. This will allow the development of strategies to detect these T cells long before they cause diabetes and will facilitate the formulation of approaches to interfere with their disease-causing activities.
| 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 |
