The scaffold protein CasL restrains membrane blebbing and promotes T cell migration.

T cell migration into inflamed tissue is a key control point in the inflammatory response and relies on integrin interactions with their endothelial ligands. Here, we identify the signaling scaffold CasL (also known as Hef1 and NEDD9) as a central regulator of integrin-dependent migration in primary T cells. We found that CasL is specifically needed for efficient migration on ICAM-1-, but not VCAM-1-coated surfaces. Although wild-type T cells migrating on ICAM-1 formed an actin-rich cell front and move smoothly, T cells lacking CasL instead formed numerous, aberrant membrane blebs. CasL was needed for the normal distribution of F-actin in the cell front and phosphorylated myosin light chain in the cell rear, suggesting that CasL regulates the cytoskeletal architecture in migrating T cells. Importantly, using an in vivo allogeneic hematopoietic transplant model, we found that CasL promotes T cell migration into inflamed peripheral tissue, but was dispensable for trafficking to secondary lymphoid organs. Together, these results indicate CasL functions to control the balance of cytoskeletal components during integrin-dependent migration and highlight the importance of integrin signaling for proper migration into inflamed tissue.