Generated single point-mutations can considerably dismantle the lymphocyteoverstimulation induced by Yersinia pseudotuberculosis superantigen

The superantigenic Yersinia pseudotuberculosis-derived mitogen (YPM) may co ntribute to severe complications in Y. pseudotuberculosis infections. Since the pathogenic mechanism of a superantigen (SAg) is based on its capabilit y for T-cell overstimulation, by introducing point mutations into YPM an at tempt was made to abrogate this effect. Six mutants studied exhibited a var iety of T-cell proliferating responses. Two had activity reduced by 80-90%, three had activity reduced by similar to 50%, and one mutant showed almost no attenuation. The SAg-associated in vitro pathogenic functions, cytotoxi c activation and the production of proinflammatory cytokines, were also dim inished, in parallel. Since these mutants were confirmed to be defective in TCR VP binding, it was possible to compare them with native YPM. Our resul ts suggested that the intensity of TCR VP binding is a crucial factor deter mining the severity of pathogenesis and that single amino acid alterations might be useful for producing immunotherapeautical agents from native YPM. (C) 1999 Academic Press.