Studies of pathogenic T cells in both animal models of autoimmune disease and spontaneously arising autoimmune disorders in man have demonstrated the selective use of particular T cell receptor (TCR) beta chain variable (V) genes. The recent characterization of a class of microbial products, termed superantigens (SA), which are mitogenic for T cells based on TCR Vbeta gene usage, suggests that microbial SA may provide the link between infection and autoimmunity. While clinically recognized syndromes attributable to SA are often characterized by shock and immunosuppression, our laboratory has recently demonstrated the immunostimulatory effects of some microbial SA on the humoral arm of the human immune system. The objective of this proposal is to analyze three proposed mechanisms by which microbial SA may function to stimulate the immune system and, by extension, may lead to autoimmunity. Specifically, we propose to investigate: 1) the mechanisms by which microbial SA promote T cell-dependent B cell activation; 2) the activation signal delivered to B cells by direct SA binding; 3) the potential for microbial SA to activate normally quiescent autoreactive T cells; 4) the role of microbial SA and microbial SA-reactive T cells in animal models of autoimmunity.