In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice

Irene Jarchum, Jason C. Baker, Tatsuya Yamada, Toshiyuki Takaki, Michele P. Marron, David V. Serreze, Teresa P. DiLorenzo

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Abstract

OBJECTIVE - CD8+ T-cells specific for islet antigens are essential for the development of type 1 diabetes in the NOD mouse model of the disease. Such T-cells can also be detected in the blood of type 1 diabetic patients, suggesting their importance in the pathogenesis of the human disease as well. The development of peptide-based therapeutic reagents that target islet-reactive CD8+ T-cells will require the identification of disease-relevant epitopes. RESEARCH DESIGN AND METHODS - We used islet-infiltrating CD8+ T-cells from HLA-A*0201 transgenic NOD mice in an interferon-γ enzyme-linked immunospot assay to identify autoantigenic peptides targeted during the spontaneous development of disease. We concentrated on insulin (Ins), which is a key target of the autoimmune response in NOD mice and patients alike. RESULTS - We found that HLA-A*0201-restricted T-cells isolated from the islets of the transgenic mice were specific for Ins1 L3-11, Ins1 B5-14, and Ins1/2 A2-10. Insulin-reactive T-cells were present in the islets of mice as young as 5 weeks of age, suggesting an important function for these specificities early in the pathogenic process. Although there was individual variation in peptide reactivity, Ins1 B5-14 and Ins1/2 A2-10 were the immunodominant epitopes. Notably, in vivo cytotoxicity to cells bearing these peptides was observed, further confirming them as important targets of the pathogenic process. CONCLUSIONS - The human versions of B5-14 and A2-10, differing from the murine peptides by only a single residue, represent excellent candidates to explore as CD8+ T-cell targets in HLA-A*0201-positive type 1 diabetic patients.

Original languageEnglish (US)
Pages (from-to)2551-2560
Number of pages10
JournalDiabetes
Volume56
Issue number10
DOIs
StatePublished - Oct 2007

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Inbred NOD Mouse
Transgenic Mice
Insulin
T-Lymphocytes
Peptides
varespladib methyl
Enzyme-Linked Immunospot Assay
Immunodominant Epitopes
HLA-A*02:01 antigen
Autoimmunity
Type 1 Diabetes Mellitus
Interferons
Epitopes
Research Design
Antigens

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Jarchum, I., Baker, J. C., Yamada, T., Takaki, T., Marron, M. P., Serreze, D. V., & DiLorenzo, T. P. (2007). In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice. Diabetes, 56(10), 2551-2560. https://doi.org/10.2337/db07-0332

In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice. / Jarchum, Irene; Baker, Jason C.; Yamada, Tatsuya; Takaki, Toshiyuki; Marron, Michele P.; Serreze, David V.; DiLorenzo, Teresa P.

In: Diabetes, Vol. 56, No. 10, 10.2007, p. 2551-2560.

Research output: Contribution to journalArticle

Jarchum, I, Baker, JC, Yamada, T, Takaki, T, Marron, MP, Serreze, DV & DiLorenzo, TP 2007, 'In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice', Diabetes, vol. 56, no. 10, pp. 2551-2560. https://doi.org/10.2337/db07-0332
Jarchum I, Baker JC, Yamada T, Takaki T, Marron MP, Serreze DV et al. In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice. Diabetes. 2007 Oct;56(10):2551-2560. https://doi.org/10.2337/db07-0332
Jarchum, Irene ; Baker, Jason C. ; Yamada, Tatsuya ; Takaki, Toshiyuki ; Marron, Michele P. ; Serreze, David V. ; DiLorenzo, Teresa P. / In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice. In: Diabetes. 2007 ; Vol. 56, No. 10. pp. 2551-2560.
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AU - Marron, Michele P.

AU - Serreze, David V.

AU - DiLorenzo, Teresa P.

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N2 - OBJECTIVE - CD8+ T-cells specific for islet antigens are essential for the development of type 1 diabetes in the NOD mouse model of the disease. Such T-cells can also be detected in the blood of type 1 diabetic patients, suggesting their importance in the pathogenesis of the human disease as well. The development of peptide-based therapeutic reagents that target islet-reactive CD8+ T-cells will require the identification of disease-relevant epitopes. RESEARCH DESIGN AND METHODS - We used islet-infiltrating CD8+ T-cells from HLA-A*0201 transgenic NOD mice in an interferon-γ enzyme-linked immunospot assay to identify autoantigenic peptides targeted during the spontaneous development of disease. We concentrated on insulin (Ins), which is a key target of the autoimmune response in NOD mice and patients alike. RESULTS - We found that HLA-A*0201-restricted T-cells isolated from the islets of the transgenic mice were specific for Ins1 L3-11, Ins1 B5-14, and Ins1/2 A2-10. Insulin-reactive T-cells were present in the islets of mice as young as 5 weeks of age, suggesting an important function for these specificities early in the pathogenic process. Although there was individual variation in peptide reactivity, Ins1 B5-14 and Ins1/2 A2-10 were the immunodominant epitopes. Notably, in vivo cytotoxicity to cells bearing these peptides was observed, further confirming them as important targets of the pathogenic process. CONCLUSIONS - The human versions of B5-14 and A2-10, differing from the murine peptides by only a single residue, represent excellent candidates to explore as CD8+ T-cell targets in HLA-A*0201-positive type 1 diabetic patients.

AB - OBJECTIVE - CD8+ T-cells specific for islet antigens are essential for the development of type 1 diabetes in the NOD mouse model of the disease. Such T-cells can also be detected in the blood of type 1 diabetic patients, suggesting their importance in the pathogenesis of the human disease as well. The development of peptide-based therapeutic reagents that target islet-reactive CD8+ T-cells will require the identification of disease-relevant epitopes. RESEARCH DESIGN AND METHODS - We used islet-infiltrating CD8+ T-cells from HLA-A*0201 transgenic NOD mice in an interferon-γ enzyme-linked immunospot assay to identify autoantigenic peptides targeted during the spontaneous development of disease. We concentrated on insulin (Ins), which is a key target of the autoimmune response in NOD mice and patients alike. RESULTS - We found that HLA-A*0201-restricted T-cells isolated from the islets of the transgenic mice were specific for Ins1 L3-11, Ins1 B5-14, and Ins1/2 A2-10. Insulin-reactive T-cells were present in the islets of mice as young as 5 weeks of age, suggesting an important function for these specificities early in the pathogenic process. Although there was individual variation in peptide reactivity, Ins1 B5-14 and Ins1/2 A2-10 were the immunodominant epitopes. Notably, in vivo cytotoxicity to cells bearing these peptides was observed, further confirming them as important targets of the pathogenic process. CONCLUSIONS - The human versions of B5-14 and A2-10, differing from the murine peptides by only a single residue, represent excellent candidates to explore as CD8+ T-cell targets in HLA-A*0201-positive type 1 diabetic patients.

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