JOURNAL ARTICLE
RESEARCH SUPPORT, N.I.H., EXTRAMURAL
RESEARCH SUPPORT, NON-U.S. GOV'T
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The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice.

Journal of Immunology 2017 December 16
Type 1 diabetes (T1D) has a strong genetic component. The insulin dependent diabetes ( Idd ) 22 locus was identified in crosses of T1D-susceptible NOD mice with the strongly T1D-resistant ALR strain. The NODcALR-( D8Mit293-D8Mit137 )/Mx (NOD- Idd22 ) recombinant congenic mouse strain was generated in which NOD mice carry the full Idd22 confidence interval. NOD- Idd22 mice exhibit almost complete protection from spontaneous T1D and a significant reduction in insulitis. Our goal was to unravel the mode of Idd22 -based protection using in vivo and in vitro models. We determined that Idd22 did not impact immune cell diabetogenicity or β cell resistance to cytotoxicity in vitro. However, NOD- Idd22 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- Idd22 mice, yet the accumulation of pathogenic CTLs in the islets was significantly reduced in NOD- Idd22 mice, correlating with disease resistance. Pancreatic endothelial cells from NOD- Idd22 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- Idd22 endothelium compared with NOD-derived endothelium. Taken together, these results provide evidence that Idd22 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.

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