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.
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.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
T P
TP
DiLorenzo
R T
RT
Graser
T
T
Ono
G J
GJ
Christianson
H D
HD
Chapman
D C
DC
Roopenian
S G
SG
Nathenson
D V
DV
Serreze
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D006183:H-2 Antigens / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009765:Obesity; D013601:T-Lymphocytes / Q000276:immunology*
D017931:DNA Primers; D006183:H-2 Antigens; C024755:H-2K(K) antigen