PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration

Wenji Piao (), Lushen Li, Vikas Saxena, Jegan Iyyathurai, Ram Lakhan, Yigang Zhang, Isadora Tadeval Lape, Christina Paluskievicz, Keli L. Hippen, Young Lee, Emma Silverman, Marina W. Shirkey, Leonardo V. Riella, Bruce R. Blazar and Jonathan S. Bromberg ()
Additional contact information
Wenji Piao: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Lushen Li: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Vikas Saxena: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Jegan Iyyathurai: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Ram Lakhan: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Yigang Zhang: Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota Cancer Center
Isadora Tadeval Lape: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
Christina Paluskievicz: University of Maryland School of Medicine
Keli L. Hippen: Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota Cancer Center
Young Lee: University of Maryland School of Medicine
Emma Silverman: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Marina W. Shirkey: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Leonardo V. Riella: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
Bruce R. Blazar: Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota Cancer Center
Jonathan S. Bromberg: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and there are contradictory data about their roles in regulatory T cell (Treg) function. Here we show activated Tregs and CD4 effector T cells (Teffs) use PD-1/PD-L1 and CD80/PD-L1, respectively, to regulate transendothelial migration across lymphatic endothelial cells (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative ligand for PD-L1), or LEC PD-L1 impairs Treg or Teff migration in vitro and in vivo. PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate zipper junctional VE-cadherin, and through NFκB-p65 to up-regulate VCAM-1 expression on LECs. CD80/PD-L1 signaling up-regulates VCAM-1 through ERK and NFκB-p65. PD-1 and CD80 blockade reduces tumor egress of PD-1high fragile Tregs and Teffs into draining lymph nodes, respectively, and promotes tumor regression. These data provide roles for PD-L1 in cell migration and immune regulation.

Date: 2022
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DOI: 10.1038/s41467-022-29930-0

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