Mucosal Addressin Cell Adhesion Molecule-1 Mediates T Cell Migration into Pancreas-Draining Lymph Nodes for Initiation of the Autoimmune Response in Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease that is caused by autoreactive T cell-mediated destruction of insulin-producing β cells in the pancreatic islets. Although naive autoreactive T cells are initially primed by islet antigens in pancreas-draining lymph nodes (pan-LNs), the adhesion molecules that recruit T cells into pan-LNs are unknown. We show that high endothelial venules in pan-LNs of young nonobese diabetic mice have a unique adhesion molecule profile that includes strong expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Anti-MAdCAM-1 antibody blocked more than 80% of the migration of naive autoreactive CD4+ T cells from blood vessels into pan-LNs. Transient blockade of MAdCAM-1 in young nonobese diabetic mice led to increased numbers of autoreactive regulatory CD4+ T cells in pan-LNs and pancreas and to long-lasting protection from T1D. These results indicate the importance of MAdCAM-1 in the development of T1D and suggest MAdCAM-1 as a potential therapeutic target for treating T1D.