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.
Spontaneous Autoimmune Diabetes in Monoclonal T Cell Nonobese Diabetic Mice
Address correspondence to Dr. Pere Santamaria, Department of Microbiology and Infectious Diseases, The University of Calgary, Faculty of Medicine, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Phone: 403-220-8735; FAX: 403-270-8520; E-mail: [email protected]
J. Verdaguer was supported by a postdoctoral fellowship from CIRIT (Comissió Interdepartamental de Reçerca i Innovació Tecnològica) Generalitat de Catalunya, Barcelona, Spain. P. Santamaria is a scholar of the Medical Research Council of Canada. This research was supported by grants from the Medical Research Council of Canada, the Natural Sciences and Engineering Council of Canada, and the Juvenile Diabetes Foundation International.
Abbreviations used in this paper: CM, complete medium; HPRT, hypoxanthine phosphoribosyl transferase; IDDM, insulin-dependent diabetes mellitus; NOD, nonobese diabetic; RAG, recombination-activating gene.
Joan Verdaguer, Dennis Schmidt, Abdelaziz Amrani, Brad Anderson, Nuzhat Averill, Pere Santamaria; Spontaneous Autoimmune Diabetes in Monoclonal T Cell Nonobese Diabetic Mice . J Exp Med 17 November 1997; 186 (10): 1663–1676. doi: https://doi.org/10.1084/jem.186.10.1663
Download citation file:
Sign in
Client Account
Sign in via your Institution
Sign in via your InstitutionSuggested Content
Email alerts
Advertisement