Proposed model for LFA-1 conformational switches triggered during lymphocyte motility on CCL21 and by TCR signals. Resting PB T cells express globally inactive LFA-1 with low affinity to ICAM-1. During motility on the immobilized chemokine, LFA-1 molecules cluster at the leading edge of the polarized T cell, and a subset of these LFA-1 molecules undergo priming and opening of their β₂ I domain, exposing the 327C epitope. This priming step is Kindlin-3 independent. The α_L I domain on both normal and Kindlin-3–deficient T cells remains in a closed conformation with low affinity to ICAM-1 and is therefore nonadhesive. When a concomitant TCR signal is encountered by a motile lymphocyte, the primed LFA-1 becomes readily responsive to an outside-in, ICAM-1–driven rearrangement event, which stabilizes the αL I domain in an open, high-affinity conformation, resulting in a firm LFA-1/ICAM-1 contact (to a bead or a DC, data not shown). This critical TCR-stimulated LFA-1/ICAM-1 bond stabilization does not take place in Kindlin-3–deficient T cells due to the inability of the LFA-1 heterodimer to properly anchor to the cytoskeleton and undergo final outside-in unclasping.