On page 1987, Semmrich and colleagues show that immune cells expressing a perpetually activated form of the integrin LFA-1 get traction at the front of the cell, but get stuck from behind. Their lagging ends prevent them from crawling through the endothelium and initiating a normal immune response.

T cells that express a constitutively activated form of the integrin LFA-1 (bottom) have restricted mobility compared to those expressing wild-type LFA-1 (top).

Integrins, such as LFA-1, are adhesive molecules that switch between active and inactive conformations and control migration of circulating immune cells to sites of infection and inflammation. LFA-1 is also required for the formation of stable interactions between T cells and antigen presenting cells (APCs). Previous studies had shown that both tumor-specific T cell responses and neutrophil migration are compromised in the absence of this integrin.

The importance of LFA-1 deactivation, however, has been less clear. In vitro studies have shown that locking LFA-1 in its activated conformation impairs both neutrophil chemotaxis and T cell activation. Semmrich et al. now confirm these findings in vivo, and show that lymphocytes from mice expressing a constitutively active LFA-1 moved more slowly than wild-type cells and failed to migrate across endothelial cell monolayers. Video microscopy revealed that these defective movements were due to an inability of the cells to release their trailing edges.

CD4+ T cell proliferation and antibody production were also impaired in these mice. The development of antigen-specific CD8+ cytotoxic T cells, by contrast, was not altered by the mutated LFA-1, but the ability of these cells to lyse target cells was decreased. The authors suggest that defects in T cell activation and function may reflect the need for serial engagement of T cell receptors with peptide–MHC complexes on APCs, a process that may be compromised by the inability to inactivate LFA-1 and thus to terminate cell–cell contacts.

Mice expressing the mutant LFA-1 closely resembled mice lacking the protein completely, suggesting that, for immune cells, letting go is just as important as grabbing on.