The Frequency and Immunodominance of Islet-Specific CD8 + T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment
Emanuela Martinuzzi 1 2 ,
Giulia Novelli 3 ,
Matthieu Scotto 1 2 ,
Philippe Blancou 4 5 ,
Jean-Marie Bach 4 5 ,
Lucy Chaillous 4 6 ,
Graziella Bruno 3 ,
Lucienne Chatenoud 1 2 ,
Peter van Endert 1 2 and
Roberto Mallone 1 2
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
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-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.
aAb, autoantibody
IA-2, insulinoma-associated protein 2
IFN-γ, γ-interferon
IGRP, islet glucose-6-phosphatase catalytic subunit-related protein
PBMC, peripheral blood mononuclear cell
PPI, preproinsulin
SFC, spot-forming cells
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,...

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

10.2337/db07-1594