Staphylococcal enterotoxin-A directly stimulates signal transduction and interferon-gamma production in psoriatic T-cell lines

Bacterial superantigens such as staphylococcal enterotoxin-A (SEA) have bee n implicated in the pathogenesis of psoriasis vulgaris. Major histocompatib ility complex (MHC) class II molecules are high affinity receptors for SEA, and T cells found in psoriatic skin lesions express high levels of MHC cla ss II. Here we address the question of whether SEA can directly activate ps oriatic T cells in the absence of professional antigen-presenting cells. We show that SEA induces i) tyrosine phosphorylation of several proteins, ii) downregulation of the T-cell receptor (TCR), and iii) production of interf eron-gamma (IFN-gamma), but not autocrine mitogenesis in CD8-positive T clo nes obtained from skin lesions of a patient with psoriasis vulgaris. Psoria tic T cells do not respond to SEA molecules if mutations are introduced in the TCR beta- or in both the two MHC class II a and beta-binding sites of S EA. Mutations in only one of the two MHC class II binding sites of SEA has different effects on T-cell activation. Thus, SEA molecules with a mutation in the MHC class II beta-binding site induce protein tyrosine phosphorylat ion, but not IFN-gamma production or co stimulation of cytokine-mediated pr oliferation. In contrast, SEA with a mutation in the MHC class II alpha-bin ding site induces IFN-gamma and a qualitatively changed tyrosine phosphoryl ation profile. Both mutations delete the costimulatory effect on cytokine-m ediated proliferation, This suggests that both MHC class II binding sites a re involved in the autopresentation of SEA by psoriatic T cells. In conclus ion, we provide evidence that SEA directly activates MHC class II-positive psoriatic T-cell lines to produce IFN-gamma, a key cytokine in the pathogen esis of psoriasis vulgaris.