Characterization of in silico Reconstruction of TCRs for Modeling Autoreactive T cells in T1D
Contact PI: Todd Brusko PhD, Sally Kent PhD, Maki Nakayama MD
Abstract
Elucidating the autoreactive T cell repertoire and function of islet-infiltrating T cells in human individuals with type 1 diabetes (T1D) is crucial for understanding the pathology of β-cell destruction and for the design of successful immunotherapies of T1D. Currently, the majority of the information concerning islet-associated T cell autoreactivity is from studies of peripheral blood of individuals at-risk for T1D, with T1D, from healthy individuals, from histological examination of pancreata from individuals with T1D and a very limited number of studies examining the T cell receptor (TCR) repertoire from human pancreata and from pancreatic draining lymph nodes. Recently, the technological barrier of islet isolation from donor individuals with T1D has been overcome and the Network of Pancreatic Organ Donors with Type 1 Diabetes (nPOD) and the Integrated Islet Distribution Program (IIDP) has been able to obtain and distribute islets from donors with T1D for study. To date, from a case of a 14 year old female with 2 years of T1D and clear histological evidence of islet infiltrate, insulin positive islets, presence of islet autoantibody and presence of high-risk HLA alleles, we have generated a large number (> 870 total) of CD4 and CD8 T cell lines and sequenced and cloned paired TCR a and b chains from islet infiltrating T cells; we have identified the epitope specificity of 2 CD4+ T cells so far. We aim to identify the autoantigenic specificity/HLA restriction and effector function of both CD4 and CD8 islet infiltrating T cells, preserve and immortalize these reagents for investigators in HIRN, and for the T1D community and, especially, for future study. Importantly, we will create T Cell Avatars for the re-direction of autoreactivity to T cell regulation in cellular therapy for T1D.
Opportunity Pool Project Sponsored by CMAI.
Awarded: 2016
Publications
- Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are Selectively Recognized by CD4(+) T Cells in Patients With Type 1 Diabetes
- Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”
- Narrowing in on the anti-β cell-specific T cells: looking ‘where the action is’
- Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes
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