Direct physical contacts with epithelial cells regulate leukocyte actin dynamics to facilitate intraepithelial motility in vivo.

Efficient immune cell migration requires physical interactions with surrounding tissues. While tissue matrix mechanics influence leukocyte motility, it is unknown how leukocytes exert pushing and pulling forces to traverse cell-dense epithelial tissues in vivo. Here, we leverage the optical transparency of larval zebrafish to identify how physical interactions with epithelial cells regulate mechanisms of neutrophil force generation to navigate cell-dense tissues. Confining forces from epithelial cells induce a mechanosensitive central actin network, mediated by Cdc42 and Wiskott-Aldrich Syndrome Protein, which exerts expansile forces on surrounding cells to dilate a path for migration. In concert, direct cell-to-cell (leukocyte-epithelial) contacts mediated by integrin ɑE recognition of epithelial cadherin generate traction forces to enable forward motility. Together, our findings identify how physical interactions with the surrounding cellular environment regulate leukocyte motility through epithelial tissue in vivo.