STAPHYLOCOCCUS ENTEROTOXIN-A MODULATES INTERLEUKIN 15-INDUCED SIGNALING AND MITOGENESIS IN HUMAN T-CELLS

T cells expressing the appropriate T-cell receptor VP chain proliferat e in response to Staphylococcus enterotoxin A (SEA) pulsed antigen-pre senting cells (APC), whereas other T cells do not (SEA ''non-responder s''). Activated human T cells express MHC class II molecules that are high affinity receptors for SEA. Here we show that, in the absence of APC, SEA induces a profound inhibition of IL-15-driven proliferation i n MHC class II+, human SEA-''responder'' T-cell lines, In contrast, pr oliferation induced by phorbol esther (PMA) was enhanced by SEA, The i nhibitory effect on cytokine-mediated mitogenesis correlates with an i nhibition of IL-2R beta expression and ligand-induced tyrosine phospho rylation of IL-2R. Cyclosporin A (CyA), an inhibitor of the protein ph osphatase (PP2B) calcineurin, strongly inhibits the SEA-induced modula tions of cytokine receptor express-Department of Clinical ion. Moreove r, CyA inhibits both the anti-mitogenic effect of SEA on cytokine-indu ced, proliferation and the pro-mitogenic effect of PMA. In contrast, i nhibitors of PP1, PP2A, protein kinase C (PE;C), phosphatidyl-inositol -3 kinase (PI-3K) and mammalian target of rapamycin (mTOR) are unable to inhibit the effects of SEA. In a SEA ''non-responder'' T-cell clone obtained from the affected skin of a patient with psoriasis vulgaris, SEA does not inhibit IL-2R beta expression and IL-15-driven prolifera tion, On the contrary, SEA enhances IL-15- and IL-2-induced proliferat ion via a CyA-sensitive pathway in this T-cell clone, In conclusion, t he present data show that (i) SEA selectively inhibits IL-15- (but not PMA-) mediated proliferation in SEA ''responder'' T cells, (ii) SEA e nhances cytokine-driven growth in psoriasis T cells with a ''non-respo nder'' phenotype, and (iii) crosstalk between SEA receptors and the IL -15R (and IL-BR) pathway is mediated via a PP2B-dependent and PP1/PP2A -, PKC-, PI-3 kinase-and mTOR-independent pathway in human T-cell line s.