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

The superantigenic Yersinia pseudotuberculosis-derived mitogen (YPM) may contribute to severe complications in Y. pseudotuberculosis infections. Since the pathogenic mechanism of a superantigen (SAg) is based on its capability for T-cell overstimulation, by introducing point mutations into YPM an attempt was made to abrogate this effect. Six mutants studied exhibited a variety 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, cytotoxic activation and the production of proinflammatory cytokines, were also diminished, in parallel. Since these mutants were confirmed to be defective in TCR VP binding, it was possible to compare them with native YPM. Our results suggested that the intensity of TCR VP binding is a crucial factor determining the severity of pathogenesis and that single amino acid alterations might be useful for producing immunotherapeautical agents from native YPM. (C) 1999 Academic Press.