The Type 1 Diabetes–Resistance Locus <i>Idd22</i> Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice

Abstract

Type 1 diabetes (T1D) has a strong genetic component. The <i>insulin dependent diabetes</i> (<i>Idd</i>)<i>22</i> locus was identified in crosses of T1D-susceptible NOD mice with the strongly T1D-resistant ALR strain. The NODcALR-(<i>D8Mit293-D8Mit137</i>)/Mx (NOD-<i>Idd22</i>) recombinant congenic mouse strain was generated in which NOD mice carry the full <i>Idd22</i> confidence interval. NOD-<i>Idd22</i> mice exhibit almost complete protection from spontaneous T1D and a significant reduction in insulitis. Our goal was to unravel the mode of <i>Idd22</i>-based protection using in vivo and in vitro models. We determined that <i>Idd22</i> did not impact immune cell diabetogenicity or β cell resistance to cytotoxicity in vitro. However, NOD-<i>Idd22</i> mice were highly protected against adoptive transfer of T1D. Transferred CTLs trafficked to the pancreatic lymph node and proliferated to the same extent in NOD and NOD-<i>Idd22</i> mice, yet the accumulation of pathogenic CTLs in the islets was significantly reduced in NOD-<i>Idd22</i> mice, correlating with disease resistance. Pancreatic endothelial cells from NOD-<i>Idd22</i> animals expressed lower levels of adhesion molecules, even in response to inflammatory stimuli. Lower adhesion molecule expression resulted in weaker adherence of T cells to NOD-<i>Idd22</i> endothelium compared with NOD-derived endothelium. Taken together, these results provide evidence that <i>Idd22</i> regulates the ability of β cell-autoreactive T cells to traffic into the pancreatic islets and may represent a new target for pharmaceutical intervention to potentially prevent T1D.