Diabetes and other autoimmune endocrine diseases

Thematic

T Cell Library Assay Identified Functional ZnT8-Specific Memory CD8+ T Cells in Patients with Type 1 Diabetes

Saturday, June 17
2:05 PM - 2:20 PM

Recent studies identified pancreatic islet antigen-specific CD8+ T cells in patients with type 1 diabetes (T1D) and healthy subjects with comparable frequencies, however the difference in the function was not fully understood. Other groups have used T cell library to assess CD4+ T cell response to pathogens or myelin autoantigens, but CD8+ T cell libraries have not been previously studied. We generated more than 8,000 CD8+ T cell libraries from PBMCs of 17 patients and 9 healthy subjects and studied its reactivity against pooled islet antigen peptides including preproinsulin, IGRP, IA-2, and ZnT8. The frequency of positive libraries responding to the islet antigens with robust IFNg production was significantly higher in the memory CD8+ fraction of T1D patients (3.83%) compared to healthy subjects (1.02%). The estimated ratio of these cells in the patients was 0.0019%. It declined over time after onset of disease (R2=0.2365, p=0.0335). In addition to IFNg, these cells produced higher levels of proinflammatory cytokines including TNF-a and IL-6. Among 17 positive libraries from 3 patients were further analyzed for reactivity to antigenic peptides and all the libraries reacted with ZnT8186-194 peptide suggesting that this is a major islet antigen recognized by CD8+ T cells. TCR sequencing analysis on the libraries revealed that there is no or minimum shared clonality of ZnT8-speicific TCRs among the patients. These results imply that the library assay is useful for analyzing the islet antigen specific-CD8+ T cells, which allows us to achieve immunological measures to evaluate the progression and intervention of disease.

Hideki Ogura

Associate Research Scientist
Department of Immunobiology, Yale University

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Paula Preston-Hurlburt

Yale University

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Kevan Herold

Professor of Immunology
Department of Immunobiology and Internal Medicine, Yale University

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T Cell Library Assay Identified Functional ZnT8-Specific Memory CD8+ T Cells in Patients with Type 1 Diabetes



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