Single Insulin-Specific CD8+ T Cells Show Characteristic Gene Expression Profiles in Human Type 1 Diabetes

  1. Christian Boitard1,2,6
  1. 1INSERM, U986, Paris, France
  2. 2Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
  3. 3CNRS-UPR 9021, Institut de Biologie Moléculaire et Cellulaire, Paris, France
  4. 4Unité de Biostatistique et Épidémiologie, Hôpital Cochin, Paris, France
  5. 5Laboratoire de Biologie Hormonale, Hôpital Cochin, Paris, France
  6. 6Service de Diabétologie, Hôpital Cochin et Hôtel Dieu, Paris, France
  1. Corresponding author: Christian Boitard, christian.boitard{at}htd.aphp.fr.

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 PPI6–14, whereas CD8+ T cells in long-standing patients recognize the B-chain peptide PPI33–42 (B9–18). 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. PPI6–14–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.

  • Received February 26, 2011.
  • Accepted September 6, 2011.

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  1. Diabetes
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