Faculty Research 1990 - 1999

Title

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 alpha chain gene rearrangement.

Document Type

Article

Publication Date

1998

Keywords

Animal, Base-Sequence, Diabetes-Mellitus-Insulin-Dependent: im, pp, pa, DNA-Primers, Gene-Rearrangement-alpha-Chain-T-Cell-Antigen-Receptor, H-2-Antigens: im, Islets-of-Langerhans: im, pa, Mice, Mice-Inbred-NOD, Obesity, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, T-Lymphocytes: im

JAX Source

Proc Natl Acad Sci U S A 1998 Oct 13;95(21):12538-43

Grant

AI07289/AI/NIAID, DK52956/DK/NIDDK, DK46266/DK/NIDDK

Abstract

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic beta 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 beta chain repertoire. In contrast, their alpha chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of Valpha17 family members frequently joined to the Jalpha42 gene segment. These results suggest that a number of the CD8(+) T cells participating in the initial phase of autoimmune beta cell destruction recognize a common structural component of Kd/peptide complexes on pancreatic beta cells, possibly a single peptide.