Kindlin-3 is required for the stabilization of TCR-stimulated LFA-1:ICAM-1 bonds critical for lymphocyte arrest and spreading on dendritic cells

Kindlin-3 is a key LFA-1 co-activator deleted in leukocyte adhesion deficiency-III (LAD-III). In the present study, we investigated the involvement of this adaptor in lymphocyte motility and TCR-triggered arrest on ICAM-1 or on dendritic cells (DCs). Kindlin-3 null primary T cells from a LAD-III patient migrated normally on the major lymph node chemokine, CCL21, and engaged in normal TCR signaling. Nevertheless, TCR activation of Kindlin-3 null T lymphocytes failed to trigger the robust LFA-1 mediated T cell spreading on ICAM-1, and on ICAM-1 expressing DCs, observed with normal lymphocytes. Kindlin-3 was also essential for cytoskeletal anchorage of the LFA-1 heterodimer and for microclustering of LFA-1 within ventral focal dots of TCR-stimulated lymphocytes spread on ICAM-1. Surprisingly, LFA-1 on Kindlin-3 null lymphocytes migrating over CCL21 acquired normal expression of an epitope associated with the conformational activation of the key headpiece domain, β I. This activated LFA-1 was highly responsive to TCR triggered ICAM-1 driven stop signals in normal T cells locomoting on CCL21, but not in their Kindlin-3 null T cell counterparts. We suggest that Kindlin-3 selectively contributes to a final TCR-triggered outside-in stabilization of bonds generated between chemokine primed LFA-1 molecules and cell-surface ICAM-1.