Single Insulin-Specific CD8+ T Cells Show Characteristic Gene Expression Profiles in Human Type 1 Diabetes
- Sandrine Luce1,2,
- François Lemonnier1,2,
- Jean-Paul Briand3,
- Joel Coste4,
- Najiba Lahlou3,5,
- Sylviane Muller3,
- Etienne Larger2,6,
- Benedita Rocha2,
- Roberto Mallone1,2 and
- Christian Boitard1,2,6⇓
- 1INSERM, U986, Paris, France
- 2Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
- 3CNRS-UPR 9021, Institut de Biologie Moléculaire et Cellulaire, Paris, France
- 4Unité de Biostatistique et Épidémiologie, Hôpital Cochin, Paris, France
- 5Laboratoire de Biologie Hormonale, Hôpital Cochin, Paris, France
- 6Service de Diabétologie, Hôpital Cochin et Hôtel Dieu, Paris, France
- Corresponding author: Christian Boitard, .
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.
- © 2011 by the American Diabetes Association.
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