HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes

Toshiyuki Takaki, Michele P. Marron, Clayton E. Mathews, Stephen T. Guttmann, Rita Bottino, Massimo Trucco, Teresa P. DiLorenzo, David V. Serreze

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

In both humans and NOD mice, particular MHC genes are primary contributors to development of the autoreactive CD4+ and CD8+ T cell responses against pancreatic β cells that cause type 1 diabetes (T1D). Association studies have suggested, but not proved, that the HLA-A*0201 MHC class I variant is an important contributor to T1D in humans. In this study, we show that transgenic expression in NOD mice of HLA-A*0201, in the absence of murine class I MHC molecules, is sufficient to mediate autoreactive CD8+ T cell responses contributing to T1D development. CD8 + T cells from the transgenic mice are cytotoxic to murine and human HLA-A*0201-positive islet cells. Hence, the murine and human islets must present one or more peptides in common. Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is one of several important T1D autoantigens in standard NOD mice. Three IGRP-derived peptides were identified as targets of diabetogenic HLA-A*0201-restricted T cells in our NOD transgenic stock. Collectively, these results indicate the utility of humanized HLA-A*0201-expressing NOD mice in the identification of T cells and autoantigens of potential relevance to human T1D. In particular, the identified antigenic peptides represent promising tools to explore the potential importance of IGRP in the development of human T1D.

Original languageEnglish (US)
Pages (from-to)3257-3265
Number of pages9
JournalJournal of Immunology
Volume176
Issue number5
StatePublished - Mar 1 2006

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Inbred NOD Mouse
Autoantigens
Type 1 Diabetes Mellitus
T-Lymphocytes
Peptides
Glucose-6-Phosphatase
Human Development
Islets of Langerhans
Transgenic Mice
HLA-A*02:01 antigen
Catalytic Domain
Genes
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Takaki, T., Marron, M. P., Mathews, C. E., Guttmann, S. T., Bottino, R., Trucco, M., ... Serreze, D. V. (2006). HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. Journal of Immunology, 176(5), 3257-3265.

HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. / Takaki, Toshiyuki; Marron, Michele P.; Mathews, Clayton E.; Guttmann, Stephen T.; Bottino, Rita; Trucco, Massimo; DiLorenzo, Teresa P.; Serreze, David V.

In: Journal of Immunology, Vol. 176, No. 5, 01.03.2006, p. 3257-3265.

Research output: Contribution to journalArticle

Takaki, T, Marron, MP, Mathews, CE, Guttmann, ST, Bottino, R, Trucco, M, DiLorenzo, TP & Serreze, DV 2006, 'HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes', Journal of Immunology, vol. 176, no. 5, pp. 3257-3265.
Takaki T, Marron MP, Mathews CE, Guttmann ST, Bottino R, Trucco M et al. HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. Journal of Immunology. 2006 Mar 1;176(5):3257-3265.
Takaki, Toshiyuki ; Marron, Michele P. ; Mathews, Clayton E. ; Guttmann, Stephen T. ; Bottino, Rita ; Trucco, Massimo ; DiLorenzo, Teresa P. ; Serreze, David V. / HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. In: Journal of Immunology. 2006 ; Vol. 176, No. 5. pp. 3257-3265.
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