An Arp2/3-cPLA ₂-NFκB axis acts as a Cell Shape Sensor to drive Homeostatic Migration of Dendritic Cells

Abstract

Dendritic cells (DCs) patrol tissues and migrate to lymph nodes for presentation of collected antigens to T cells. This process is needed to initiate immune responses against infectious agents as well as to maintain tolerance to tissue self-antigens at steady state. In both cases, DC migration to lymph nodes requires the upregulation of the chemokine receptor CCR7. It is well-known that upon infection, CCR7 expression is induced by microbial and inflammatory components released within the tissue environment. However, the environmental signals that trigger CCR7 expression and homeostatic DC migration to lymph nodes at steady state remain unidentified. Here we show that the changes in cell shape experienced by tissue patrolling DCs are sufficient to induce CCR7 expression at their surface and their migration to lymph nodes. Cell shape sensing requires ARP2/3-dependent activation of the lipid metabolism enzyme cytosolic phospholipase 2 (cPLA ₂) acting upstream of NFκB. Activation of this shape-sensitive axis reprograms DCs towards a specific immunoregulatory phenotype that is distinct from the one induced by microbes and leads to T cell hypo-responsiveness. We propose that cell shape sensing might constitute the long sought-after signal that drives homeostatic DC migration to lymph nodes for maintenance of tolerance to self.

HIGHLIGHTS

• - Dendritic cells express the lymph node guiding chemokine receptor CCR7 upon activation of a cell shape sensor.

• - Cell shape sensing is driven by an ARP2/3-cPLA ₂ signaling axis that activates NFκ upstream of CCR7 expression.

• - Activation of this shape-sensitive axis reprograms dendritic cells towards a specific immunoregulatory phenotype, distinct from the one induced by microbes.

• - Cell shape sensing might constitute the long sought-after signal that drives homeostatic dendritic cells migration for maintenance of tolerance to self.