Signaling through the tetraspanin CD82 triggers its association with the cytoskeleton leading to sustained morphological changes and T cell activation

In this report, we provide new evidence of a crosstalk between T cell activ ation and adhesion processes through a functional cytokeleton. We show that CD82 signaling induces longlasting adhesion, spreading and development of membrane extensions, involving actin polymerization. Addition of various co -stimuli (phorbol 12-myristate 13-acetate or monoclonal antibodies to CD3 o r CD2) increases the CD82-induced morphological alterations and, reciprocal ly, CD82 engagement synergizes with these stimuli to induce T cell activati on as indicated by both primary tyrosine phosphorylation and IL-2 productio n. Different kinases are involved in both processes. CD82 co-signaling invo lves src kinases including p56 lck. On the other hand, the CD82-induced alt erations of cell morphology are negatively regulated by cAMP-dependent kina ses independently of activation of src kinases. Simultaneously with cytoske letal rearrangements, we observed an inducible association of CD82 with the cytoskeletal matrix. In addition, the potentiating and stabilizing effects induced by CD82 crosslinking on tyrosine phosphorylation were abolished by cytoskeleton-disrupting agents. These results suggest that the actin polym erization triggered by CD82, through its ability to associate with the cyto skeletal matrix, is the primary step involved in the CD82 induced costimula tory activity. Our data provide further evidence for a direct role of the a ctin cytoskeleton as a major component for sustained signal transduction in T cells and suggest that tetraspanins could be "membrane organizers" conne cting both surface and intracellular molecules.