Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration.
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.
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
C Colin
CC
Brinkman
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Daiki
D
Iwami
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Molly K
MK
Hritzo
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Yanbao
Y
Xiong
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Sarwat
S
Ahmad
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Thomas
T
Simon
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA.
Keli L
KL
Hippen
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA.
Bruce R
BR
Blazar
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Jonathan S
JS
Bromberg
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology / Q000601:surgery; D016381:Islets of Langerhans Transplantation; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D042601:Lymphatic Vessels / Q000166:cytology / Q000276:immunology; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000235:genetics / Q000276:immunology*; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology*; D014184:Transplantation, Homologous; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology
C505699:Ltbr protein, mouse; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1