HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes

Matthieu Scotto; Georgia Afonso; Thomas Østerbye; Etienne Larger; Sandrine Luce; Cécile Raverdy; Giulia Novelli; Graziella Bruno; Céline Gonfroy-Leymarie; Odile Launay; François A Lemonnier; Søren Buus; Jean-Claude Carel; Christian Boitard; Roberto Mallone

doi:10.2337/db12-0136

HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes

Matthieu Scotto, Georgia Afonso, Thomas Østerbye, Etienne Larger, Sandrine Luce, Cécile Raverdy, Giulia Novelli, Graziella Bruno, Céline Gonfroy-Leymarie, Odile Launay, François A Lemonnier, Søren Buus, Jean-Claude Carel, Christian Boitard, Roberto Mallone

12 Citationer (Scopus)

Abstract

The cartography of β-cell epitopes targeted by CD8(+) T cells in type 1 diabetic (T1D) patients remains largely confined to the common HLA-A2 restriction. We aimed to identify β-cell epitopes restricted by the HLA-B7 (B*07:02) molecule, which is associated with mild T1D protection. Using DNA immunization on HLA-B7-transgenic mice and prediction algorithms, we identified GAD and preproinsulin candidate epitopes. Interferon-γ (IFN-γ) enzyme-linked immunospot assays on peripheral blood mononuclear cells showed that most candidates were recognized by new-onset T1D patients, but not by type 2 diabetic and healthy subjects. Some epitopes were highly immunodominant and specific to either T1D children (GAD(530-538); 44% T cell-positive patients) or adults (GAD(311-320); 38%). All epitopes displayed weak binding affinity and stability for HLA-B7 compared with HLA-A2-restricted ones, a general feature of HLA-B7. Single-cell PCR analysis on β-cell-specific (HLA-B7 tetramer-positive) T cells revealed uniform IFN-γ and transforming growth factor-β (TGF-β) mRNA expression, different from HLA-A2-restricted T cells. We conclude that HLA-B7-restricted islet epitopes display weak HLA-binding profiles, are different in T1D children and adults, and are recognized by IFN-γ(+)TGF-β(+)CD8(+) T cells. These features may explain the T1D-protective effect of HLA-B7. The novel epitopes identified should find valuable applications for immune staging of HLA-B7(+) individuals.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	61
Udgave nummer	10
Sider (fra-til)	2546-2555
Antal sider	10
ISSN	0046-0192
DOI	https://doi.org/10.2337/db12-0136
Status	Udgivet - okt. 2012

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10.2337/db12-0136

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Scotto, M., Afonso, G., Østerbye, T., Larger, E., Luce, S., Raverdy, C., Novelli, G., Bruno, G., Gonfroy-Leymarie, C., Launay, O., Lemonnier, F. A., Buus, S., Carel, J.-C., Boitard, C., & Mallone, R. (2012). HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes. Diabetes, 61(10), 2546-2555. https://doi.org/10.2337/db12-0136

Scotto, M, Afonso, G, Østerbye, T, Larger, E, Luce, S, Raverdy, C, Novelli, G, Bruno, G, Gonfroy-Leymarie, C, Launay, O, Lemonnier, FA, Buus, S, Carel, J-C, Boitard, C & Mallone, R 2012, 'HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes', Diabetes, bind 61, nr. 10, s. 2546-2555. https://doi.org/10.2337/db12-0136

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title = "HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes",

abstract = "The cartography of β-cell epitopes targeted by CD8(+) T cells in type 1 diabetic (T1D) patients remains largely confined to the common HLA-A2 restriction. We aimed to identify β-cell epitopes restricted by the HLA-B7 (B*07:02) molecule, which is associated with mild T1D protection. Using DNA immunization on HLA-B7-transgenic mice and prediction algorithms, we identified GAD and preproinsulin candidate epitopes. Interferon-γ (IFN-γ) enzyme-linked immunospot assays on peripheral blood mononuclear cells showed that most candidates were recognized by new-onset T1D patients, but not by type 2 diabetic and healthy subjects. Some epitopes were highly immunodominant and specific to either T1D children (GAD(530-538); 44% T cell-positive patients) or adults (GAD(311-320); 38%). All epitopes displayed weak binding affinity and stability for HLA-B7 compared with HLA-A2-restricted ones, a general feature of HLA-B7. Single-cell PCR analysis on β-cell-specific (HLA-B7 tetramer-positive) T cells revealed uniform IFN-γ and transforming growth factor-β (TGF-β) mRNA expression, different from HLA-A2-restricted T cells. We conclude that HLA-B7-restricted islet epitopes display weak HLA-binding profiles, are different in T1D children and adults, and are recognized by IFN-γ(+)TGF-β(+)CD8(+) T cells. These features may explain the T1D-protective effect of HLA-B7. The novel epitopes identified should find valuable applications for immune staging of HLA-B7(+) individuals.",

keywords = "Adolescent, Adult, Aged, Animals, CD8-Positive T-Lymphocytes, Child, Child, Preschool, Diabetes Mellitus, Type 1, Epitopes, Female, HLA-B7 Antigen, Humans, Insulin-Secreting Cells, Interferon-gamma, Leukocytes, Mononuclear, Male, Mice, Middle Aged, Transforming Growth Factor beta",

author = "Matthieu Scotto and Georgia Afonso and Thomas {\O}sterbye and Etienne Larger and Sandrine Luce and C{\'e}cile Raverdy and Giulia Novelli and Graziella Bruno and C{\'e}line Gonfroy-Leymarie and Odile Launay and Lemonnier, {Fran{\c c}ois A} and S{\o}ren Buus and Jean-Claude Carel and Christian Boitard and Roberto Mallone",

year = "2012",

month = oct,

doi = "10.2337/db12-0136",

language = "English",

volume = "61",

pages = "2546--2555",

journal = "Diabetes",

issn = "0046-0192",

publisher = "American Diabetes Association",

number = "10",

}

TY - JOUR

T1 - HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes

AU - Scotto, Matthieu

AU - Afonso, Georgia

AU - Østerbye, Thomas

AU - Larger, Etienne

AU - Luce, Sandrine

AU - Raverdy, Cécile

AU - Novelli, Giulia

AU - Bruno, Graziella

AU - Gonfroy-Leymarie, Céline

AU - Launay, Odile

AU - Lemonnier, François A

AU - Buus, Søren

AU - Carel, Jean-Claude

AU - Boitard, Christian

AU - Mallone, Roberto

PY - 2012/10

Y1 - 2012/10

N2 - The cartography of β-cell epitopes targeted by CD8(+) T cells in type 1 diabetic (T1D) patients remains largely confined to the common HLA-A2 restriction. We aimed to identify β-cell epitopes restricted by the HLA-B7 (B*07:02) molecule, which is associated with mild T1D protection. Using DNA immunization on HLA-B7-transgenic mice and prediction algorithms, we identified GAD and preproinsulin candidate epitopes. Interferon-γ (IFN-γ) enzyme-linked immunospot assays on peripheral blood mononuclear cells showed that most candidates were recognized by new-onset T1D patients, but not by type 2 diabetic and healthy subjects. Some epitopes were highly immunodominant and specific to either T1D children (GAD(530-538); 44% T cell-positive patients) or adults (GAD(311-320); 38%). All epitopes displayed weak binding affinity and stability for HLA-B7 compared with HLA-A2-restricted ones, a general feature of HLA-B7. Single-cell PCR analysis on β-cell-specific (HLA-B7 tetramer-positive) T cells revealed uniform IFN-γ and transforming growth factor-β (TGF-β) mRNA expression, different from HLA-A2-restricted T cells. We conclude that HLA-B7-restricted islet epitopes display weak HLA-binding profiles, are different in T1D children and adults, and are recognized by IFN-γ(+)TGF-β(+)CD8(+) T cells. These features may explain the T1D-protective effect of HLA-B7. The novel epitopes identified should find valuable applications for immune staging of HLA-B7(+) individuals.

AB - The cartography of β-cell epitopes targeted by CD8(+) T cells in type 1 diabetic (T1D) patients remains largely confined to the common HLA-A2 restriction. We aimed to identify β-cell epitopes restricted by the HLA-B7 (B*07:02) molecule, which is associated with mild T1D protection. Using DNA immunization on HLA-B7-transgenic mice and prediction algorithms, we identified GAD and preproinsulin candidate epitopes. Interferon-γ (IFN-γ) enzyme-linked immunospot assays on peripheral blood mononuclear cells showed that most candidates were recognized by new-onset T1D patients, but not by type 2 diabetic and healthy subjects. Some epitopes were highly immunodominant and specific to either T1D children (GAD(530-538); 44% T cell-positive patients) or adults (GAD(311-320); 38%). All epitopes displayed weak binding affinity and stability for HLA-B7 compared with HLA-A2-restricted ones, a general feature of HLA-B7. Single-cell PCR analysis on β-cell-specific (HLA-B7 tetramer-positive) T cells revealed uniform IFN-γ and transforming growth factor-β (TGF-β) mRNA expression, different from HLA-A2-restricted T cells. We conclude that HLA-B7-restricted islet epitopes display weak HLA-binding profiles, are different in T1D children and adults, and are recognized by IFN-γ(+)TGF-β(+)CD8(+) T cells. These features may explain the T1D-protective effect of HLA-B7. The novel epitopes identified should find valuable applications for immune staging of HLA-B7(+) individuals.

KW - Adolescent

KW - Adult

KW - Aged

KW - Animals

KW - CD8-Positive T-Lymphocytes

KW - Child

KW - Child, Preschool

KW - Diabetes Mellitus, Type 1

KW - Epitopes

KW - Female

KW - HLA-B7 Antigen

KW - Humans

KW - Insulin-Secreting Cells

KW - Interferon-gamma

KW - Leukocytes, Mononuclear

KW - Male

KW - Mice

KW - Middle Aged

KW - Transforming Growth Factor beta

U2 - 10.2337/db12-0136

DO - 10.2337/db12-0136

M3 - Journal article

C2 - 22997432

SN - 0046-0192

VL - 61

SP - 2546

EP - 2555

JO - Diabetes

JF - Diabetes

IS - 10

ER -

HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes

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