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J. Exp. Med.,
Volume 186, Number 10, November 17, 1997 1663-1676
By
From the Department of Microbiology and Infectious Diseases, and Julia McFarlane Diabetes Research
Centre, The University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada T2N 4N1
It has been established that insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic
(NOD) mice results from a CD4+ and CD8+ T cell-dependent autoimmune process directed
against the pancreatic beta cells. The precise roles that beta cell-reactive CD8+ and CD4+ T cells
play in the disease process, however, remain ill defined. Here we have investigated whether naive beta cell-specific CD8+ and CD4+ T cells can spontaneously accumulate in pancreatic islets, differentiate into effector cells, and destroy beta cells in the absence of other T cell specificities. This was done by introducing Kd- or I-Ag7-restricted beta cell-specific T cell receptor
(TCR) transgenes that are highly diabetogenic in NOD mice (8.3- and 4.1-TCR, respectively), into recombination-activating gene (RAG)-2-deficient NOD mice, which cannot rearrange endogenous TCR genes and thus bear monoclonal TCR repertoires. We show that
while RAG-2
/ 4.1-NOD mice, which only bear beta cell-specific CD4+ T cells, develop
diabetes as early and as frequently as RAG-2+ 4.1-NOD mice, RAG-2/ 8.3-NOD mice,
which only bear beta cell-specific CD8+ T cells, develop diabetes less frequently and significantly later than RAG-2+ 8.3-NOD mice. The monoclonal CD8+ T cells of RAG-2/ 8.3-NOD mice mature properly, proliferate vigorously in response to antigenic stimulation in vitro,
and can differentiate into beta cell-cytotoxic T cells in vivo, but do not efficiently accumulate in islets in the absence of a CD4+ T cell-derived signal, which can be provided by splenic
CD4+ T cells from nontransgenic NOD mice. These results demonstrate that naive beta cell-
specific CD8+ and CD4+ T cells can trigger diabetes in the absence of other T or B cell specificities, but suggest that efficient recruitment of naive diabetogenic beta cell-reactive CD8+ T cells
to islets requires the assistance of beta cell-reactive CD4+ T cells.
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