IL-13 Mediated Regulation of Islet-Reactive T Cells (143.44)

Abstract

Abstract Immunotherapy with the beta cell antigen glutamic acid decarboxylase (GAD65) or GAD65 peptides delays the onset of type 1 diabetes (T1D) in NOD mice, while alum formulated rGAD65 may be therapeutic in human T1D; nevertheless, the regulatory mechanisms involved in each therapy may be distinct. Here, we sought to discover the factors that contribute to GAD65 peptide 524-538 (p524)-mediated protection from T1D in NOD mice and to determine if IL-13 produced by p524-specific T cells could regulate pathogenic islet-reactive T cells. IL-13 produced by p524-reactive T cells directly modulated IFN-g production by spontaneously arising GAD65 530-543-specific Th1 cells in NOD mice and rIL-13 inhibited proliferative responses of islet-reactive BDC2.5 clonotypic T cells. Contrary to previous observations, both CD4+ and CD8+ T cells in the peripheral lymphoid compartment of NOD and C57BL/6 mice expressed the receptor subunit required for IL-13 signaling, IL-13Rα1. Interestingly, the number of IL13Rα1+ T cells was highest in pancreatic lymph nodes, as compared to inguinal lymph node or splenic T cells, and this expression was uniquely diminished in pancreatic lymph nodes of older prediabetic NOD. Thus, IL-13 may be an important mechanism for regulation of autoreactive T cells in the early stages of insulitis. The loss of IL-13Rα1 expression on T cells in the draining nodes of the pancreas may reflect fading regional immune regulation and progression from insulitis to overt T1D.