Distinctive signaling pathways through CD82 and beta1 integrins in human T cells

CD82, a member of tetraspan family (tetraspanin), is a multifunctional molecule that is involved in cell activation, costimulation, and cell spreading of T cells. Here we show that immobilized anti-CD82 monoclonal antibody (mAb) as well as anti-alpha4beta1 integrin mAb induced tyrosine phosphorylation of pp105/Crk-associated substrate lymphocyte type (Cas-L) in human peripheral T cells and H9 cells. Furthermore, one of anti-CD82 mAb (8E4), which induces homotypic aggregation of T cells and H9 cells but has no costimulatory activity, partially inhibited very late antigen (VLA)-4 integrin ligand-mediated costimulation of T cells, whereas it failed to inhibit VLA-5 integrin ligand-mediated costimulation. To further elucidate the relationship between CD82- and VLA-4-mediated signaling pathways we defined the IL-2 production by the costimulation of Jurkat T cells with marginal amount of Cas-L, and subsequently found that mAb against CD82 had strong costimulatory activity to CD3/TCR, whereas mAb against beta1 failed to do so in those cells. We have further demonstrated that this discrepancy between beta1 integrin- and CD82-mediated costimulation partly lies in differential activation of NF-AT, AP-1, and NF-kappaB in Jurkat T cells. In this study, although some functional overlap exists, we provide evidence for distinctive signaling of CD82- and beta1 integrin-mediated costimulation at the transcriptional level of IL-2 gene.