Spontaneous Autoimmune Diabetes in Monoclonal T Cell Nonobese Diabetic Mice

Abstract

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.

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

“…Mice, bacteria and infection 8.3 NOD mice, expressing the rearranged T cell receptor genes of the diabetogenic CTL clone NY8.3, have been previously described [23] and were provided by P. Santamaria (University of Calgary, Calgary, AB, Canada). 8.3 NOD mice and NOD mice (Jackson Laboratory, Bar Harbor, ME, USA) were housed and bred under SPF conditions at the Child and Family Research Institute (Vancouver, BC, Canada), and used between 4 and 12 weeks of age.…”

“…8.3 NOD CD8 + T cells recognise an immuno-dominant peptide from IGRP, termed IGRP 206-214 , a protein expressed by pancreatic beta cells, and these cells are representative of a significant fraction of CD8 + T cells in pancreatic islets at the onset of inflammation [23,28,29]. Adoptive transfer of IGRP-specific (islet antigen) CD8 + T cells [26] into infected NOD mice confirmed an increase in the proliferation and activation of these cells in the pancreatic LNs (Fig.…”

Identification of naturally processed peptides bound to the class I MHC molecule H‐2Kd of normal and TAP‐deficient cells

“…Starting with the pioneering work of Rammensee and colleagues [5,9], Kd has been widely studied, and Kd-specific immune responses described in a number of experimental systems. These include CD8 T cell responses: (1) against viral and bacterial pathogens [6,[19][20][21][22]; (2) in the NOD mouse model of diabetic autoimmunity [23][24][25][26][27]; and, (3), to tumor antigens [28][29][30][31]. Despite these many studies, the number of identified endogenously processed peptides selected by Kd is small.…”

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

“…Moreover, injection of an islet-specific CD4 + T cell clone was found to accelerate diabetes in young NOD mice [6]. Thus, a signal derived from CD4 + T cells seems to be required for efficient accumulation of autoreactive T cells in islets of Langerhans [7,8].…”