The frequency and immunodominance of islet-specific CD8+ T-cell responses change after type 1 diabetes diagnosis and treatment.
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.


METHODS
We took advantage of a recently validated islet-specific CD8(+) T-cell gamma-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.
Martinuzzi
Emanuela
E
INSERM U580, Paris, France.
Novelli
Giulia
G
Scotto
Matthieu
M
Blancou
Philippe
P
Bach
Jean-Marie
JM
Chaillous
Lucy
L
Bruno
Graziella
G
Chatenoud
Lucienne
L
van Endert
Peter
P
Mallone
Roberto
R
D000293:Adolescent; D000328:Adult; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003384:Coxsackievirus Infections / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005952:Glucose-6-Phosphatase / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D011498:Protein Precursors / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000939:Epitopes; D015789:HLA-A2 Antigen; D007328:Insulin; D011498:Protein Precursors; C013737:preproinsulin; D005952:Glucose-6-Phosphatase; D005968:Glutamate Decarboxylase