CD8+ T Cell Tolerance in Nonobese Diabetic Mice Is Restored by Insulin-Dependent Diabetes Resistance Alleles

Abstract

Although candidate genes controlling autoimmune disease can now be identified, a major challenge that remains is defining the resulting cellular events mediated by each locus. In the current study we have used NOD-InsHA transgenic mice that express the influenza hemagglutinin (HA) as an islet Ag to compare the fate of HA-specific CD8+ T cells in diabetes susceptible NOD-InsHA mice with that observed in diabetes-resistant congenic mice having protective alleles at insulin-dependent diabetes (Idd) 3, Idd5.1, and Idd5.2 (Idd3/5 strain) or at Idd9.1, Idd9.2, and Idd9.3 (Idd9 strain). We demonstrate that protection from diabetes in each case is correlated with functional tolerance of endogenous islet-specific CD8+ T cells. However, by following the fate of naive, CFSE-labeled, islet Ag-specific CD8+ (HA-specific clone-4) or CD4+ (BDC2.5) T cells, we observed that tolerance is achieved differently in each protected strain. In Idd3/5 mice, tolerance occurs during the initial activation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes where CD25+ regulatory T cells (Tregs) effectively prevent their accumulation. In contrast, resistance alleles in Idd9 mice do not prevent the accumulation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes, indicating that tolerance occurs at a later checkpoint. These results underscore the variety of ways that autoimmunity can be prevented and identify the elimination of islet-specific CD8+ T cells as a common indicator of high-level protection.

Partial versus Full Allogeneic Hemopoietic Chimerization Is a Preferential Means to Inhibit Type 1 Diabetes as the Latter Induces Generalized Immunosuppression

“…Another study subsequently found, unlike in other strains, transplantation tolerance to allogeneic skin grafts is not established in NOD mice by CD40/CD154 blockade accompanied by donor-specific transfusion of splenocytes (39). This may be explained in part by the finding that unlike the case in nonautoimmune prone control strains, peripheral CD8 T cells in NOD mice are relatively defective in ability to undergo deletion upon high levels of antigenic stimulation (40,41). Additionally, donorreactive CD8 T cells have been shown to be a barrier to establishment of allogeneic bone marrow chimerism (42).…”

Targeted Disruption of CD38 Accelerates Autoimmune Diabetes in NOD/Lt Mice by Enhancing Autoimmunity in an ADP-Ribosyltransferase 2-Dependent Fashion

“…Because no genetic segregation analysis has been done previously to identify potential 129/Sv-derived Idd resistance loci, one might conjecture that a protective locus in the congenic region of Chromosome 5 may exist that interacts epistatically with another Idd in the Chromosome 7 region to boost protection to an extent even greater than seen in Chromosome 7 monogenic stocks carrying CBA or C57L alleles. Reports of synergistic (and sometimes unexpected) interactions among unlinked Idd regions are becoming more common, as for example, restoration of T cell tolerance (53) or induction of autoimmune biliary disease (54) in NOD bicongenic stocks.…”

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

“…Islets were isolated as previously described (44). Briefly, pancreata were cut into small pieces using fine scissors and digested in 2 mg/ml collagenase P (Roche Diagnostics) and 2 g/ml DNase I (Roche Diagnostics) at 37°C for 20 min.…”