The Type 1 Diabetes-Resistance locus Idd22 Controls Trafficking of Autoreactive Cytotoxic T Lymphocytes into the Pancreatic Islets of NOD Mice1
| Autor: | Whitener, Robert L., Knight, Lisa Gallo, Li, Jianwei, Knapp, Sarah, Zhang, Shuyao, Annamalai, Mani, Pliner, Vadim M, Fu, Dongtao, Radichev, Ilian, Amatya, Christina, Savinov, Alexei, Yurdagul, Arif, Yuan, Shuai, Glawe, John, Kevil, Christopher G., Chen, Jing, Stimpson, Scott E., Mathews, Clayton E |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Endothelial Cells
Autoimmunity Mice Inbred Strains Mice SCID Cytotoxicity Tests Immunologic Adoptive Transfer Article Cell Line Specific Pathogen-Free Organisms Chemotaxis Leukocyte Islets of Langerhans Mice Mice Congenic Diabetes Mellitus Type 1 Mice Inbred NOD Cell Adhesion Animals Female Cell Adhesion Molecules Crosses Genetic Disease Resistance T-Lymphocytes Cytotoxic |
| Popis: | Type 1 Diabetes (T1D) has a strong genetic component. The Insulin dependent diabetes 22 (Idd22) locus was identified in crosses of T1D-susceptible NOD mice with the strongly T1D-resistant ALR strain. The NOD-Idd22 recombinant congenic mouse strain was generated where 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 cytoxicity in vitro. However, NOD-Idd22 mice were highly protected against adoptive transfer of T1D. Transferred CTL trafficked to the pancreatic lymph node (PLN) and proliferated to the same extent in NOD and NOD-Idd22 mice yet, the accumulation of pathogenic CTL 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 as compared to 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. |
| Databáze: | OpenAIRE |
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