Department of Vascular Surgery, Tianjin Medical University Second Hospital, Tianjin 300211, China.
Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Int J Mol Sci. 2024 Oct 22;25(21):11350. doi: 10.3390/ijms252111350.
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.
1 型糖尿病（T1D）是一种自身免疫性疾病，由自身反应性 T 细胞介导的胰岛中胰岛素产生β细胞的破坏引起。尽管初始时幼稚的自身反应性 T 细胞在胰腺引流淋巴结（pan-LN）中被胰岛抗原激活，但将 T 细胞募集到 pan-LN 的黏附分子尚不清楚。我们发现，年轻的非肥胖型糖尿病小鼠 pan-LN 中的高内皮小静脉具有独特的黏附分子谱，包括黏膜地址素细胞黏附分子-1（MAdCAM-1）的强表达。抗 MAdCAM-1 抗体阻断了超过 80%的幼稚自身反应性 CD4 T 细胞从血管进入 pan-LN 的迁移。在年轻的非肥胖型糖尿病小鼠中短暂阻断 MAdCAM-1 导致 pan-LN 和胰腺中自身反应性调节性 CD4 T 细胞数量增加，并长期预防 T1D。这些结果表明 MAdCAM-1 在 T1D 的发展中的重要性，并提示 MAdCAM-1 可能是治疗 T1D 的潜在治疗靶点。
