Human CD4 and human major histocompatibility complex class II (DQ6) transgenic mice: Supersensitivity to superantigen-induced septic shock

Abstract

Rodents are significantly less sensitive to enterotoxin-induced shock, and are thus not valid human disease models. Here, we describe a mouse strain carrying the human CD4 and human major histocompatibility complex (MHC) class II (DQ6) transgenes in an endogenous CD4- and CD8-deficient background. T lymphocytes from these animals react to minute amounts (10-100 times less than control mice) of staphylococcal enterotoxin B (SEB) in vitro, similar to concentrations to which human cells react. In vivo, these double-transgenic, double-knockout mice succumb to normally sublethal amounts of SEB. This sensitivity is not due to a biased T cell receptor Vβ repertoire, increased T cell reactivity, or increased sensitivity to macrophage-derived cytokines. Rather, tumor necrosis factor (TNF)-α production by T cells and serum levels of TNF-α correlate precisely with the clinical syndrome, showing a biphasic T cell-dependent response. These data show that both human CD4 and MHC class II molecules can render mice supersensitive to superantigen-induced septic shock syndrome. This animal model mimics the progression of septic shock in man by transforming normally resistant mice into hypersensitive SEB responders, a trait that is characteristic of humans. Mice that have been humanized by exchanging autochthonous superantigen ligands by their human equivalents may be useful to decipher superantigen responses in vivo and to assess the pathogenesis of superantigen-associated diseases.