PD-L1 Reverse Signaling in Dermal Dendritic Cells Promotes Dendritic Cell Migration Required for Skin Immunity

Cell Rep. 2020 Oct 13;33(2):108258. doi: 10.1016/j.celrep.2020.108258.

Abstract

Although the function of the extracellular region of programmed death ligand 1 (PD-L1) through its interactions with PD-1 on T cells is well studied, little is understood regarding the intracellular domain of PD-L1. Here, we outline a major role for PD-L1 intracellular signaling in the control of dendritic cell (DC) migration from the skin to the draining lymph node (dLN). Using a mutant mouse model, we identify a TSS signaling motif within the intracellular domain of PD-L1. The TSS motif proves critical for chemokine-mediated DC migration to the dLN during inflammation. This loss of DC migration, in the PD-L1 TSS mutant, leads to a significant decline in T cell priming when DC trafficking is required for antigen delivery to the dLN. Finally, the TSS motif is required for chemokine receptor signaling downstream of the Gα subunit of the heterotrimeric G protein complex, ERK phosphorylation, and actin polymerization in DCs.

Keywords: CCR7 signaling; G alpha activation; MAPK signaling; PD-L1 reverse signaling; actin polymerization; dendritic cell migration; dendritic cell trafficking; dermal dendritic cell; infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amino Acids / genetics
  • Animals
  • B7-H1 Antigen / chemistry
  • B7-H1 Antigen / deficiency
  • B7-H1 Antigen / metabolism*
  • Base Sequence
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Count
  • Cell Movement* / drug effects
  • Chemokine CCL21 / pharmacology
  • Chemotaxis / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism*
  • Dermis / cytology*
  • Exons / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Proteins / metabolism
  • Immunity* / drug effects
  • Lymph Nodes / metabolism
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Phosphorylation / drug effects
  • Poly I-C / pharmacology
  • Polymerization
  • Protein Domains
  • Receptors, CCR7 / metabolism
  • Signal Transduction* / drug effects

Substances

  • Actins
  • Amino Acids
  • B7-H1 Antigen
  • Ccr7 protein, mouse
  • Chemokine CCL21
  • Receptors, CCR7
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Proteins
  • Poly I-C