Myo10-dependent leading-edge coordination maintains physical coherence of migrating dendritic cells

Abstract

Dendritic cells (DCs) are the principal leukocytes responsible for priming T cells. DC migration though geometrically complex tissue environments is crucial for initiating robust and spatiotemporally coordinated activation of adaptive immune responses. However, our understanding of the molecular mechanisms that govern physical navigation of DCs remains incomplete. Here we identify the unconventional myosin Myo10 as a critical regulator of DC trafficking. We show that loss of Myo10 attenuates FITC-induced contact hypersensitivity and reduces the efficiency of in vivo DC migration and egress from dermal explants but notably has no effect on antigen uptake or in vitro T cell priming. We further find that the migration defects of Myo10-deficient cells are exacerbated by increasing geometrical complexity. Mechanistically, Myo10 promotes physical coherence and coordinated leading edge dynamics via its interaction with lamellipodin, which subsequently drives VASP-mediated actin polymerization. Together, our findings establish a vital Myo10-lamellipodin-VASP axis essential for spatiotemporal DC navigation through restrictive microenvironments, providing critical insights into the biophysical regulation of immune surveillance.