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The integrin aL(32 (LFA-1, CD 11 a/CD 18) mediates leukocyte adhesion and migration that are required for a functional immune system. It is known that inside-out signaling triggers aL(32 conformational changes, which affect its ligand-binding affinity. At least three aL(32 affinity states (low, intermediate, and high) were described. Talin is a four-point-one ezrin radixin moesin (FERM)-domain containing cytoplasmic protein that connects aL(32 to the actin filament. The talin head domain is also known to activate aLP2 ligand binding. However, it remains to be determined whether talin promotes an intermediate or high affinity aL|32. In the first part of this study using transfectants and T cells, we showed that talin induced an intermediate affinity aL(32 that adhered constitutively to its ligand intercellular adhesion molecule (ICAM)-l but not ICAM-3. Adhesion to ICAM-3 was induced when an additional exogenous activating agent was included. Similar profiles were observed with soluble ICAMs. In addition, the intermediate affinity aL(32 induced by talin allowed adhesion and migration of T cells on immobilized ICAMs. Kindlins are also FERM-domain containing proteins that have been reported to regulate integrin function. In the second part of this study, we showed that kindlin3 co-activates aLp2 together with talin, and that its pleckstrin homology (PH) domain and F3 subdomain are required in the process. Interestingly, kindlin3-overexpressed T cells showed reduced migration on ICAM-1. Immunofluorescence staining suggest that kindlin3 and talin both localize at the leading edge of migratory T cells. It remains to be determined how kindlin3 reduces the migration of T cells. It would also be interesting to investigate at the molecular level the cooperativity of kindlin3 and talin in the regulation of CLL$2 function. ATTENTION: The Singapore Copyright Act applies to the use of this document. Nanyang Technological University Library

Investigating the roles of cytoplasmic proteins talin and kindlin3 in integrin LFA-1 activation