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, Jonathan S. Bromberg

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number2176
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by NIH grants R37AI062765, R01 AI114496, and P01 AI153003 to J.S.B.; RO1 HL155114 and R37AI34495 to B.R.B.; R01 HL11879 and P01 CA 065493 to B.R.B. and K.L.H. We thank Dr. Xiaoxuan Fan, Bryan Han, and Karen Underwood from UMB-Flow Core Facility for excellent help for flow cell sorting.

Publisher Copyright:
© 2022, The Author(s).

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