Programmed death ligand 1 intracellular interactions with STAT3 and focal adhesion protein Paxillin facilitate lymphatic endothelial cell remodeling

Lymphatic endothelial cells (LECs) comprise lymphatic capillaries and vessels that guide immune cells to lymph nodes (LNs) and form the subcapsular sinus and cortical and medullary lymphatic structures of the LN. During an active immune response, the lymphatics remodel to accommodate the influx of i...

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Published in:The Journal of biological chemistry 2022-12, Vol.298 (12), p.102694-102694, Article 102694
Main Authors: Schafer, Johnathon B., Lucas, Erin D., Dzieciatkowska, Monika, Forward, Tadg, Tamburini, Beth A. Jirón
Format: Article
Language:English
Subjects:
Animals
B7-H1 Antigen - genetics
B7-H1 Antigen - metabolism
Cellular movement
Endothelial Cells
F-actin
Immunology
Lymph node
Lymphatic endothelial cell
Lymphoid Tissue - metabolism
Mass spectrometry
Mice
Mutation
Paxillin
Paxillin - metabolism
PD-L1
Reverse-signaling
STAT3
Tumor Necrosis Factor-alpha - metabolism
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Summary:Lymphatic endothelial cells (LECs) comprise lymphatic capillaries and vessels that guide immune cells to lymph nodes (LNs) and form the subcapsular sinus and cortical and medullary lymphatic structures of the LN. During an active immune response, the lymphatics remodel to accommodate the influx of immune cells from the tissue, but factors involved in remodeling are unclear. Here, we determined that a TSS motif within the cytoplasmic domain of programmed death ligand 1 (PD-L1), expressed by LECs in the LN, participates in lymphatic remodeling. Mutation of the TSS motif to AAA does not affect surface expression of PD-L1, but instead causes defects in LN cortical and medullary lymphatic organization following immunostimulant, Poly I:C, administration in vivo. Supporting this observation, in vitro treatment of the LEC cell line, SVEC4-10, with cytokines TNFα and IFNα significantly impeded SVEC4-10 movement in the presence of the TSS-AAA cytoplasmic mutation. The cellular movement defects coincided with reduced F-actin polymerization, consistent with differences previously found in dendritic cells. Here, in addition to loss of actin polymerization, we define STAT3 and Paxillin as important PD-L1 binding partners. STAT3 and Paxillin were previously demonstrated to be important at focal adhesions for cellular motility. We further demonstrate the PD-L1 TSS-AAA motif mutation reduced the amount of pSTAT3 and Paxillin bound to PD-L1 both before and after exposure to TNFα and IFNα. Together, these findings highlight PD-L1 as an important component of a membrane complex that is involved in cellular motility, which leads to defects in lymphatic organization.
ISSN:0021-9258
1083-351X
DOI:10.1016/j.jbc.2022.102694