Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration

• Published in: Nature communications Vol. 7; no. 1; p. 12021
• Main Authors: Brinkman, C. Colin, Iwami, Daiki, Hritzo, Molly K., Xiong, Yanbao, Ahmad, Sarwat, Simon, Thomas, Hippen, Keli L., Blazar, Bruce R., Bromberg, Jonathan S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-06-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1617; 631/250/1619/554/1898/1271; 631/80/84; 631/80/86; Animals; Cell adhesion & migration; Chemokines; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - immunology; Diabetes Mellitus, Experimental - mortality; Diabetes Mellitus, Experimental - therapy; Endothelial Cells - cytology; Endothelial Cells - immunology; Gene Expression Regulation; Graft Rejection - genetics; Graft Rejection - immunology; Graft Rejection - pathology; Graft Survival - genetics; Humanities and Social Sciences; Islets of Langerhans - immunology; Islets of Langerhans - surgery; Islets of Langerhans Transplantation; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymphatic Vessels - cytology; Lymphatic Vessels - immunology; Lymphocytes; Lymphotoxin alpha1, beta2 Heterotrimer - genetics; Lymphotoxin alpha1, beta2 Heterotrimer - immunology; Lymphotoxin beta Receptor - genetics; Lymphotoxin beta Receptor - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; NF-kappa B - genetics; NF-kappa B - immunology; Science; Science (multidisciplinary); Signal Transduction; Survival Analysis; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; Transendothelial and Transepithelial Migration - immunology; Transplantation, Homologous; Transplants & implants; Tumor necrosis factor-TNF; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - immunology; United States > US; Maryland; Baltimore Maryland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12021

Regulatory T cells (Tregs) are essential to suppress unwanted immunity or inflammation. After islet allo-transplant Tregs must migrate from blood to allograft, then via afferent lymphatics to draining LN to protect allografts. Here we show that Tregs but not non-Treg T cells use lymphotoxin (LT) during migration from allograft to draining LN, and that LT deficiency or blockade prevents normal migration and allograft protection. Treg LTαβ rapidly modulates cytoskeletal and membrane structure of lymphatic endothelial cells; dependent on VCAM-1 and non-canonical NFκB signalling via LTβR. These results demonstrate a form of T-cell migration used only by Treg in tissues that serves an important role in their suppressive function and is a unique therapeutic focus for modulating suppression.
Lymphotoxin regulates lymphoid organ architecture and adhesion molecules involved in lymphocyte trafficking. Here the authors show that lymphotoxin produced by regulatory T cells promotes their migration to the draining lymph nodes by engaging its cognate receptor on lymphatic endothelial cells.