Figures Alraies et al 2024

Immune cells experience large deformation events while patrolling their environment. These cell shape changes arise from the continuous 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 is controlled by the lipid metabolism enzyme cPLA₂, requires nuclear envelop unfolding and tension and is finely tuned by the Arp2/3 actin nucleation complex. We further show that shape sensing through the Arp2/3-cPLA₂ axis controls Ikkb-NFkB-dependent transcriptional reprogramming of dendritic cells, which licenses them for migration to lymph nodes to exert their homeostatic tolerogenic function. Our results show 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 the balance between tolerance and immunity.