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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 21; pp. 12538 - 12543
• Main Authors: DiLorenzo, Teresa P., Graser, Robert T., Ono, Toshiro, Christianson, Gregory J., Chapman, Harold D., Roopenian, Derry C., Nathenson, Stanley G., Serreze, David V.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 13-10-1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Biological Sciences; Cell lines; Diabetes; Diabetes complications; Diabetes mellitus; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - physiopathology; DNA Primers; Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; Genes; H-2 Antigens - immunology; Immunology; Islet cells; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Mice; Mice, Inbred NOD; Obesity; Prediabetic state; Rodents; T cell antigen receptors; T lymphocytes; T-Lymphocytes - immunology; Type 1 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.21.12538

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-2Kd, 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 Vα 17 family members frequently joined to the Jα 42 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 Kd/peptide complexes on pancreatic β cells, possibly a single peptide.