Model of LFA-1 activation at the IS. (A) Actin-dependent regulation of LFA-1 valency. Ongoing F-actin flow (left) in T cells responding to a polarized TCR stimulus drives activation of LFA-1 at the IS. Activated LFA-1 then binds ICAM-1, leading to synaptic enrichment. Arrested F-actin dynamics (right) abrogates activation of LFA-1, allowing passive diffusion of unligated LFA-1 away from the IS. (B) Actin-dependent regulation of LFA-1 affinity. (1) Inactive LFA-1 exists in a bent conformation on the T cell surface. (2) Inside-out signaling events downstream of TCR engagement lead to recruitment of talin and F-actin to the integrin β tail. This allows for the segregation of the α and β tails and the unbending of LFA-1 to yield the extended conformation. (3) F-actin flow generates tensile force on the LFA-1 β tail (green arrow), facilitating further tail separation and resulting in swingout of the hybrid domain and induction of the open (high affinity) form of LFA-1. (4) The open αI domain primes the molecule for binding of ICAM-1, which through induced fit and tension-based mechanisms (green arrows) stabilizes LFA-1 in the high affinity, ligand-bound conformation. Alternatively, LFA-1 affinity maturation can proceed through an ICAM-1–bound, extended conformation (3′) in which ICAM-1 weakly interacts with LFA-1 and induces the open head domain before application of force; force then stabilizes this interaction. After loss of force on the β chain, ligand unbinding may preferentially occur through the 3′ step, in which there is no stabilization of the open I domain and therefore much lower affinity for ICAM-1. Alternatively, in the absence of force, LFA-1 does not undergo the priming step to the unligated, open conformation. Regular turnover of LFA-1– ICAM-1 complexes would then lead to loss of bound ICAM-1.