RAC REGULATES INTEGRIN-MEDIATED SPREADING AND INCREASED ADHESION OF T-LYMPHOCYTES

Leukocyte adhesion to the extracellular matrix (ECM) is tightly contro lled and is vital for the immune response. Circulating lymphocytes lea ve the bloodstream and adhere to ECM components at sites of inflammati on and lymphoid tissues. Mechanisms for regulating T-lymphocyte-ECM ad hesion include (i) an alteration in the affinity of cell surface integ rin receptors for their extracellular ligands and (ii) an alteration o f events following postreceptor occupancy (e.g., cell spreading). Wher eas H-Ras and R-Ras were previously shown to affect T-cell adhesion by altering the affinity state df the integrin receptors, no signaling m olecule has been identified for the second mechanism. In this study, w e demonstrated that expression of an activated mutant of Rac triggered dramatic spreading of T cells and their increased adhesion on immobil ized fibronectin in an integrin-dependent manner. This effect was not mimicked by expression of activated mutant forms of Rho, Cdc42, H-Ras, oi ARF6, indicating the unique role of pac in this event. The Rac-ind uced spreading was accompanied by specific cytoskeletal rearrangements ; Also, a clustering of integrins at sites of cell adhesion and at the peripheral edges of spread cells was observed. We demonstrate that ex pression of RacV12 did not alter the level of expression of cell surfa ce integrins or the affinity state of the integrin receptors. Moreover , our results indicate that Rac plays a role in the regulation of T-ce ll adhesion by a mechanism involving cell spreading, rather than by al tering the level of expression or the affinity of the integrin recepto rs. Furthermore, we show that the Rac-mediated signaling pathway leadi ng to spreading of T lymphocytes did not require activation of c-Jun k inase, serum response factor, or pp70(S6) (kinase) but appeared to inv olve a phospholipid kinase.