The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

  1. Emanuela Martinuzzi12,
  2. Giulia Novelli3,
  3. Matthieu Scotto12,
  4. Philippe Blancou45,
  5. Jean-Marie Bach45,
  6. Lucy Chaillous46,
  7. Graziella Bruno3,
  8. Lucienne Chatenoud12,
  9. Peter van Endert12 and
  10. Roberto Mallone12
  1. 1INSERM, U580, Paris, France
  2. 2Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France
  3. 3Università di Torino, Dipartimento di Medicina Interna, Torino, Italy
  4. 4INRA, Immuno-Endocrinology Unit, ENVN, Nantes, France
  5. 5Université de Nantes, Nantes, France
  6. 6CHU de Nantes, Hôpital Hôtel-Dieu, Clinique d'Endocrinologie, Nantes, France
  1. Corresponding authors: Roberto Mallone, MD, PhD, INSERM U561, Hôpital Saint Vincent de Paul, 82 Ave. Denfert Rochereau, 75674 Paris Cedex 14, France. E-mail: roberto.mallone{at}inserm.fr. Or Peter van Endert, MD, INSERM U580, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: vanendert{at}necker.fr

Abstract

OBJECTIVE—Islet-reactive CD8+ T-cells play a key role in the pathogenesis of type 1 diabetes in the NOD mouse. The predominant T-cell specificities change over time, but whether similar shifts also occur after clinical diagnosis and insulin treatment in type 1 diabetic patients is unknown.

RESEARCH DESIGN AND METHODS—We took advantage of a recently validated islet-specific CD8+ T-cell γ-interferon enzyme-linked immunospot (ISL8Spot) assay to follow responses against preproinsulin (PPI), GAD, insulinoma-associated protein 2 (IA-2), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes in 15 HLA-A2+ adult type 1 diabetic patients close to diagnosis and at a second time point 7–16 months later.

RESULTS—CD8+ T-cell reactivities were less frequent at follow-up, as 28.6% of responses tested positive at type 1 diabetes diagnosis vs. 13.2% after a median of 11 months (P = 0.003). While GAD and IA-2 autoantibody (aAb) titers were unchanged in 75% of cases, the fraction of patients responding to PPI and/or GAD epitopes by ISL8Spot decreased from 60–67 to 20% (P < 0.02). The previously subdominant IA-2206–214 and IGRP265–273 peptides were newly targeted, thus becoming the immunodominant epitopes.

CONCLUSIONS—Shifts both in frequency and in immunodominance of CD8+ T-cell responses occur more rapidly than do changes in aAb titers. These different kinetics may suggest complementary clinical applications for T-cell and aAb measurements.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 27 February 2008. DOI: 10.2337/db07-1594.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • See accompanying commentary, p. 1156.

    • Accepted February 18, 2008.
    • Received November 11, 2007.
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  1. Diabetes vol. 57 no. 5 1312-1320
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