Actin works both sides of the immunological synapse

Antigen-presenting cells (APCs) activate T cells by forming a specialized contact site called the immunological synapse (IS). The T cell receptor (TCR) and its downstream signaling molecules cluster in the center of the IS, surrounded by a ring of integrin molecules such as LFA-1, which lower the threshold for T cell priming by both tightly adhering to ligands on the surface of the APC and by activating downstream signaling pathways of their own. Two papers now reveal that the actin cytoskeleton on both sides of the IS promotes the full activation of LFA-1 in order to enhance T cell priming (1, 2). Stimulation of the TCR induces the T cell's F-actin network to fl ow toward the center of the IS. Jan Burkhardt and colleagues at the University of Pennsylvania in Philadelphia previously found that this centripetal fl ow is required to sustain downstream calcium signaling (3). The forces generated by the fl ow might also support mechanical signaling events at the IS. Whether the TCR itself is capable of mecha-notransduction remains controversial but, in other cell types, integrins have been suggested to alter their conformation and ligand af-fi nity in response to mechanical forces. " We decided to ask whether the actin fl ow causes conformational changes in LFA-1, " Burkhardt says. Led by graduate students Drew Comrie and Alex Babich, Burkhardt and colleagues initially used conformation-specifi c antibodies to examine the distribution of the inactive, intermediate, and fully active forms of LFA-1 at the IS (1). " LFA-1's conforma-tional intermediates are not distributed uniformly across the synapse, " Burkhardt explains. " The more active forms are located more centrally. " Freezing the centripetal fl ow of actin disrupted this organization so that the different conformations of LFA-1 became randomly distributed. Moreover, inhibiting actin dynamics lowered the total amount of LFA-1 recruited to the IS and reduced the proportion of molecules in the active conformation. " So the actin flow causes a net accumulation of LFA-1 and induces a conformational change to the high-affi nity form, " Burkhardt says. By increasing both the valency and affi n-ity of LFA-1, the actin fl ow helped ICAM-1, the integrin's ligand on APCs, bind and accumulate at the IS. However, the researchers discovered, ICAM-1 in turn affects the behavior of LFA-1. The inte-grin was strongly activated when T cells attached to surface bound ICAM-1 but not when they were stimulated by soluble …