Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor α chain gene rearrangement

Teresa P. DiLorenzo, R. T. Graser, T. Ono, G. J. Christianson, H. D. Chapman, D. C. Roopenian, S. G. Nathenson, D. V. Serreze

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Abstract

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic β cells. Although both major histocompatibility complex class I-restricted CD8+ and class II-restricted CD4+ T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic CD8+ T cells responsible, we isolated and propagated in vitro CD8+ T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-2K(d), and showed a diverse T cell receptor β chain repertoire. In contrast, their α chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of Vα17 family members frequently joined to the Jα42 gene segment. These results suggest that a number of the CD8+ T cells participating in the initial phase of autoimmune β cell destruction recognize a common structural component of K(d)/peptide complexes on pancreatic β cells, possibly a single peptide.

Original languageEnglish (US)
Pages (from-to)12538-12543
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number21
DOIs
StatePublished - Oct 13 1998

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T-Cell Receptor Genes
Inbred NOD Mouse
Gene Rearrangement
Major Histocompatibility Complex
T-Lymphocytes
Type 1 Diabetes Mellitus
Complementarity Determining Regions
Peptides
Amino Acid Motifs
T-Lymphocyte Subsets
T-Cell Antigen Receptor
Islets of Langerhans
Amino Acid Sequence
Genes

ASJC Scopus subject areas

  • Genetics
  • General

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Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor α chain gene rearrangement. / DiLorenzo, Teresa P.; Graser, R. T.; Ono, T.; Christianson, G. J.; Chapman, H. D.; Roopenian, D. C.; Nathenson, S. G.; Serreze, D. V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 21, 13.10.1998, p. 12538-12543.

Research output: Contribution to journalArticle

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