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We previously reported that Yersinia pseudotuberculosis-derived mitogen (YPM) acts as a superantigen to human T cells. In this study, we assessed the superantigenicity and toxicity of YPM using murine experimental models. YPM activated T cells to produce interleukin-2 in a major histocompatibility complex class II molecule-dependent manner. The T-cell blasts induced by YPM expressed T-cell receptor (TCR) beta-chain variable region (Vbeta)7, Vbeta8.1, Vbeta8.2 and Vbeta8.3. The injection of YPM into mice pre-sensitized with D-galactosamine induced lethal shock. This shock was blocked by the injection of monoclonal antibodies (mAbs) to CD4, TCR Vbeta7 plus Vbeta8, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), but not by injection to CD8 or unrelated Vbeta. These results indicate that YPM-induced shock requires the presence of CD4+ T cells bearing TCR Vbeta7 and Vbeta8, and that endogenous TNF-alpha and IFN-gamma mediate the lethal effects.

In 1993 there was substantial progress in superantigen research. The following are the main achievements. (i) The life cycle of an exogenous mouse mammary tumor virus, MMTV (SW), has been clearly eluciated. (ii) X-ray crystallography of toxic shock syndrome toxin 1 has been completed. (iii) The involvement of a superantigen encoded by an endogenous mouse mammary tumor virus, Mtv-51, in the development of a B cell lymphoma has been shown in SJL mice. However, there are many unsolved questions. For example, (i) are there endogenous superantigens in man? (ii) is there any role for superantigens in the development of autoimmunity? (iii) what is the three dimensional structure of superantigens encoded by mouse mammary tumor viruses? In the near future superantigens will be exploited for therapeutic purposes in the area of autoimmunity and cancer.

This article puts forward the hypothesis that the I-J genetic restriction observed between certain downregulatory (suppressor) T cells and antigen presenting cells is due to an endogenous superantigen analogous to the mouse mammary tumour virus (Mtv) products encoded by the open reading frames in the 3' long terminal repeat (LTR) of mtv's. In its weak form this hypothesis asserts that the I-J genetic restriction is due to an endogenous superantigen ligand on antigen presenting cells, which crosslinks the V beta and/or V alpha chains of certain T cell receptors (TCR) with major histocompatibility complex (MHC) class II, and that MHC together with this superantigen ligand causes positive selection of T cells bearing the appropriate I-J+ TCR in the thymus. In the periphery these T cells recognize peptide/MHC complex in the presence of the superantigen. In its strong form the hypothesis states that this superantigen ligand for TCR and MHC is encoded by integrated virus genome, e.g. Mtv. These possibilities can now be approached experimentally and their exploration may uncover one of the ways in which T cells are assigned to different functions, including downregulation.