The staphylococcal enterotoxins are members of a family of structurally related Gram-positive pyrogenic exotoxins with similar functional activities. These enterotoxins are involved in the toxic shack syndromes, and are a major cause of food-borne intoxication. These toxins are also immunosuppressive, and this immunosuppressive activity may be involved in the toxic shock disease process. Understanding the nature of the interaction of these toxins and the immune system in general, and the mechanism of immunosuppressive activity specifically, is a matter of continuing interest. It is becoming increasingly clear that the immunosuppressive activity of these toxins is due, at least in part, to the activation of regulatory T cells. The administration of staphylococcal enterotoxin B (SEB) to lymphoid cells in vitro leads to the generation of multiple populations of these suppressor T cells. Certain of these populations appear to function by producing genetically-restricted soluble mediators with immunosuppressive activity. This proposal is directed toward a further analysis of cellular interactions which occur following the activation of these suppressive T cell populations. Studies will be carried out with purified lymphoid cell populations in an effort to determine the precise source of the suppressor factors. In addition, cell culture techniques will be employed in an effort to determine the cellular target of these cells and factors. Efforts will be made to assess the molecular nature of the immunosuppressive effect. This proposal is also directed toward a further localization of the epitopes present within the toxin which are responsible for the capacity to stimulate lymphoid cells. The investigators will employ overlapping synthetic peptides which span the region they have determined to possess the biological activity in an effort to localize the epitopes. In addition, they will employ multiple strategies for the generation of recombinant toxin fragments. The analysis of the activities of these fragments, together with the results from the analysis of the synthetic peptides, should permit a determination of the location and the number of epitopes with biological activity.
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