Cell Shape Sensing Licenses Dendritic Cells for Homeostatic Migration to Lymph Nodes

Immune cells experience large deformation events while patrolling their environment. These cell shape changes arise from the physical constraints encountered during migration within and between tissues. It has become increasingly clear that these cells can survive and adapt to these changes in cell shape using dedicated shape sensing pathways. However, how shape sensing impacts their behavior and function remains largely unknown. Here we identify a shape sensing mechanism that couples dendritic cell motility to expression of CCR7, the chemokine receptor guiding their migration from the periphery to lymph nodes. We found that this mechanism relies on the lipid metabolism enzyme cPLA ₂ , requires nuclear envelop unfolding and tension and is finely tuned by the Arp2/3 actin nucleation complex. We further observed that shape sensing through the Arp2/3-cPLA ₂ axis leads to Ikkb-NFkB-dependent transcriptional reprogramming of dendritic cells, which was shown to control their migration to lymph node and tolerogenic function at steady-state. Our results highlight that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties, revealing the contribution of the physical properties of tissues to adaptive immunity.