TY - JOUR
T1 - PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration
AU - Piao, Wenji
AU - Li, Lushen
AU - Saxena, Vikas
AU - Iyyathurai, Jegan
AU - Lakhan, Ram
AU - Zhang, Yigang
AU - Lape, Isadora Tadeval
AU - Paluskievicz, Christina
AU - Hippen, Keli L.
AU - Lee, Young
AU - Silverman, Emma
AU - Shirkey, Marina W.
AU - Riella, Leonardo V.
AU - Blazar, Bruce R.
AU - Bromberg, Jonathan S.
N1 - 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).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-29930-0
DO - 10.1038/s41467-022-29930-0
M3 - Article
C2 - 35449134
AN - SCOPUS:85128602578
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2176
ER -
