T-cell migration is a complex highly coordinated process that involves cell adhesion to the high endothelial venules or to the extracellular matrix by surface receptor/ligand interactions, cytoskeletal rearrangements, and phosphorylation-dependent signaling cascades. The mechanism(s) that regulates T-cell migration is of considerable relevance for understanding the pathogenesis of various diseases, such as chronic inflammatory diseases and cancer metastasis. This study was designed to identify potential involvement of STAT3, a latent transcription factor, in mediating integrin-induced T-cell migration. Using our previously characterized in vitro model for lymphocyte migration, we demonstrate that STAT3 is activated and translocated to the nucleus during the process of active motility of Hut78 T-lymphoma cells triggered via LFA-1. Blocking STAT3 signaling by multiple approaches inhibited LFA-1-induced T-cell locomotion via destabilization of microtubules and post-translational modification of tubulin. Here, we show that STAT3 physically interacts with stathmin to regulate microtubule dynamics in migrating T-cells. These observations strongly indicate that STAT3 is critically important for T-cell migration and associated signaling events.Efficient operation of the adaptive immune system requires migration of T-lymphocytes from the vascular compartment across tissue barriers and through the extracellular matrix. This process involves a series of integrin ligand-receptor interactions (1) that initially retards lymphocyte flow and ultimately leads to arrest and diapedesis across the endothelium (2, 3). T-cells utilize the integrin, lymphocyte function-associated antigen-1 (LFA-1), 3 when migrating in response to chemoattractants across the vasculature into lymph nodes or inflamed tissues (1, 4, 5). By engagement with ligands from the intercellular adhesion molecule group (ICAMs), in particular ICAM-1, LFA-1 also provides a strong adhesive force to promote and stabilize T-cell and antigen-presenting cell conjugate formation. We have demonstrated that LFA-1 transduces a variety of transmembrane signals in crawling T-cells involving protein kinase C activation and cytoskeletal rearrangement (4, 6 -9). However, the exact sequence of downstream integrin-mediated signaling events resulting in cytoskeletal rearrangements and cell locomotion is not fully understood.T-cell migration involves cross-talk between integrins and the cytoskeleton, coordinated changes in the cytoskeleton, and the controlled formation and dispersal of adhesion sites (10). Motile lymphocytes develop trailing extensions, which contain cytoskeletal and signaling elements (11). Microtubules (MTs) are essential components of the cytoskeleton and are important for many aspects of mammalian cell responses, including cell division, growth, migration, and signaling (12)(13)(14). Whereas the actin cytoskeleton provides the driving force at the cell front, the MT network assumes a regulatory function in coordinating rear retraction (15). MT retraction into the ...

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