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

¹ INSERM, U580, Paris, France
² Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France
³ Università di Torino, Dipartimento di Medicina Interna, Torino, Italy
⁴ INRA, Immuno-Endocrinology Unit, ENVN, Nantes, France
⁵ Université de Nantes, Nantes, France
⁶ CHU de Nantes, Hôpital Hôtel-Dieu, Clinique d'Endocrinologie, Nantes, France

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

Key Words: aAb, autoantibody • IA-2, insulinoma-associated protein 2 • IFN-, -interferon • IGRP, islet glucose-6-phosphatase catalytic subunit-related protein • PBMC, peripheral blood mononuclear cell • PPI, preproinsulin • SFC, spot-forming cells

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 -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-2_206–214 and IGRP_265–273 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.

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