Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration

Abstract

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways.

Remodeling our concept of chemokine receptor function: From monomers to oligomers

“…Differences between CCL19 and CCL21 in promoting CCR7 endocytosis into early endosomes have been also reported . It is also known that whereas CCL19 and CCL21 trigger similar SHP2 phosphorylation and association to CCR7, CCL21 was stronger than CCL19 in promoting cytosolic activity of SHP2 in T cells …”

“…A cyclic helix‐forming peptide mimetic, based on the human CCR2 dimerization region, specifically blocked CCL2‐mediated monocyte migration, suggesting an important role of TM‐I in CCR2 dimerization . In the case of CCR7, single point mutations in vicinity of the NPXXY motif of TM‐VII greatly reduced CCR7 oligomerization and cell migration toward CCL19 and CCL21 gradients . In conclusion, several lines of evidence support the importance of receptor dimerization/oligomerization for chemokine function and indicate a role for residues in the transmembrane domains in the complex formation.…”

Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

“…Instead, it seems that CXCL14 synergized with gp120 in the viral entry response, irrespective of whether CXCL12 was present. Recent evidence suggests that chemokine-mediated receptor oligomerization is required for efficient chemokine responses (70). Although more experiments are needed to clarify the exact mechanism, it is possible that CXCL14-mediated CXCR4 clustering may facilitate gp120 binding and, thus, X4 HIV-1 infection.…”

Topical Prostaglandin E Analog Restores Defective Dendritic Cell–Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice

“…The role of PGE 2 in CCR7 expression has been controversial. Recently, PGE 2 has been shown to induce CCR7 receptor oligomerization rather than expression, resulting in an efficient signaling pathway that enhances migration (13). However, together with other soluble mediators such as tumor necrosis factor-α, IL-1β, and IL-6, PGE 2 has been shown to increase CCR7 expression (37).…”

“…During this process, DCs require maturation, a process associated with upregulation of class II MHC and costimulatory molecules (CD80, CD86, CD40) (12) and consequent migration to lymph nodes in a CC-chemokine receptor 7 (CCR7)–dependent response to its ligands CCL19 and CCL21 (13). In addition, the lipid mediator prostaglandin E 2 (PGE 2 ) has been shown to be a key factor for DC maturation and migration through CCR7 (14).…”