Single insulin-specific CD8 + T cells show characteristic gene expression profiles in human type 1 diabetes

Abstract

OBJECTIVE - Both the early steps and the high recurrence of autoimmunity once the disease is established are unexplained in human type 1 diabetes. Because CD8 + T cells are central and insulin is a key autoantigen in the disease process, our objective was to characterize HLA class I-restricted autoreactive CD8 + T cells specific for preproinsulin (PPI) in recent-onset and long-standing type 1 diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS - We used HLA-A*02:01 tetramers complexed to PPI peptides to enumerate circulating PPI-specific CD8 + T cells in patients and characterize them using membrane markers and single-cell PCR. RESULTS - Most autoreactive CD8 + T cells detected in recent-onset type 1 diabetic patients are specific for leader sequence peptides, notably PPI 6-14, whereas CD8 + T cells in long-standing patients recognize the B-chain peptide PPI 33-42 (B 9-18). Both CD8 +T-cell specificities are predominantly naïve, central, and effector memory cells, and their gene expression profile differs from cytomegalovirus-specific CD8 + T cells. PPI 6-14-specific CD8 +T cells detected in one healthy control displayed Il-10 mRNA expression, which was not observed in diabetic patients. CONCLUSIONS - PPI-specific CD8 + T cells in type 1 diabetic patients include central memory and target different epitopes in new-onset versus long-standing disease. Our data support the hypothesis that insulin therapy may contribute to the expansion of autoreactive CD8 + T cells in the long term. © 2011 by the American Diabetes Association.