T-cell recognition of antigen displayed by an antigen-presenting cell (APC) results in the formation of an area of close membrane contact between the two cells, known as the immunological synapse. Once the immunological synapse has formed, the T-cell stops migrating, changes shape, and forms a tight and long-lasting conjugate with the APC. How is antigen recognition linked to the cytoskeletal changes required for this to occur? A French group has now shown that inactivation of Ezrin-Radixin-Moesin (ERM) proteins through a Vav1–Rac1 pathway leads to relaxation of the T-cell cytoskeleton and favours conjugate formation with APCs.

ERM proteins act as general crosslinkers between the actin network near the cell surface and the plasma membrane, and have previously been shown to be inactivated after antigen recognition by the T-cell receptor (TCR). To investigate this pathway further, the authors focused on Rho GTPases, which are known to be involved in controlling T-cell morphology. Using constitutively activated and dominant-negative mutants of the small GTPases Rac1 and Cdc42, they showed that Rac1, but not Cdc42, is involved in the dephosphorylation and inactivation of ERM proteins downstream of the TCR triggering.

The guanine-nucleotide exchange factor Vav1 is involved in controlling actin cytoskeleton reorganization in T cells after TCR ligation, so Faure et al. tested whether Vav1 could act to link TCR ligation to ERM-protein inactivation. In contrast to wild-type cells, Vav1−/− T cells were resistant to TCR-induced ERM-protein dephosphorylation, indicating that Vav1 is the main exchange factor connecting TCR ligation to Rac1 activation and ERM-protein dephosphorylation.

What effect does this Vav1–Rac1-dependent inactivation of ERM proteins have on T-cell morphology and function? Using a dominant-negative ERM molecule to mimic ERM inactivation, the authors showed that in the absence of ERM protein activity, the actin network close to the plasma membrane was disorganized, the rigidity of the T-cell membrane was reduced and T cells showed an enhanced capacity to form conjugates with APCs.

So, through activation of Rac1, Vav1 mediates inactivation of ERM proteins after TCR ligation, leading to morphological changes including relaxation of the cytoskeleton in T cells. This enables them to interact with APCs more efficiently and so generate an effective immune response.