Endocrine Abstracts

The NOD (non-obese diabetic) mouse remains the best experimental model of type I diabetes. We have previously described several thymic dysfunctions in these animals, including the presence of giant perivascular spaces (PVS) with arrest of mature T cells (including Treg cells) and partial impairment on fibronectin/VLA-5-dependent NOD thymocyte migration. Herein, we further studied the role of extracellular matrix (ECM) ligands, alone or in combination with the chemokine CXCL12 in NOD thymocyte migration. Intrathymic contents of CXCL12, fibronectin and laminin were evaluated by immunohistochemistry and the expression of corresponding receptors was assessed by flow cytometry. Thymocyte migration was assessed by transwell chambers and transendothelial migration evaluated through an endothelial cell monolayer. NOD thymocytes expressed much lower VLA-5 than C57BL/6 thymocytes. This defect was particularly severe in CD4⁺ thymocytes expressing Foxp3, thus in keeping with the arrest of Foxp3⁺ cells within the NOD giant PVS, as defined by immmunohistochemistry. Accordingly, lower percentages of NOD Treg cells were observed in the spleen and subcutaneous lymph nodes. We also observed an enhancement in CXCL12, laminin and fibronectin deposition and co-localization in the NOD thymus. Furthermore, we detected altered expression of the CXCL12 receptor CXCR4 and the laminin receptor VLA-6, as well as enhanced migratory capacity of NOD thymocytes towards these molecules, combined or alone. Moreover, transendothelial migration of NOD thymocytes was diminished in the presence of exogenous fibronectin. Our data unravel the existence of multiple cell migration-related abnormalities in NOD thymocytes, comprising both down- and up-regulation of specific migratory responses. It remains to be demonstrated if these events are correlated to the appearance of autoimmunity in NOD mice.