The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice

• Published in: The Journal of immunology (1950) 2017-12, Vol.199 (12), p.3991-4000
• Main Authors: Whitener, Robert L, Gallo Knight, Lisa, Li, Jianwei, Knapp, Sarah, Zhang, Shuyao, Annamalai, Mani, Pliner, Vadim M, Fu, Dongtao, Radichev, Ilian, Amatya, Christina, Savinov, Alexei, Yurdagul, Jr, Arif, Yuan, Shuai, Glawe, John, Kevil, Christopher G, Chen, Jing, Stimpson, Scott E, Mathews, Clayton E
• Format: Article
• Language: English
• Subjects: Adhesion; Adoptive Transfer; Animal models; Animals; Autoimmunity - genetics; Cell Adhesion; Cell adhesion molecules; Cell Adhesion Molecules - metabolism; Cell Line; Chemotaxis, Leukocyte - genetics; Chemotaxis, Leukocyte - physiology; Crosses, Genetic; Cytotoxicity; Cytotoxicity Tests, Immunologic; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; Disease Resistance; Endothelial cells; Endothelial Cells - immunology; Endothelial Cells - metabolism; Endothelium; Female; Inflammation; Insulin; Insulitis; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Lymph nodes; Lymphocytes; Lymphocytes T; Mice; Mice, Congenic; Mice, Inbred NOD; Mice, Inbred Strains; Mice, SCID; Pancreas; Rodents; Specific Pathogen-Free Organisms; Strain; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - pathology; T-Lymphocytes, Cytotoxic - transplantation; Trafficking
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1602037

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