SYNERGISTIC EFFECT BETWEEN CD40 AND CLASS-II SIGNALS OVERCOME THE REQUIREMENT FOR CLASS-II DIMERIZATION IN SUPERANTIGEN-INDUCED CYTOKINE GENE-EXPRESSION

Although staphylococcal enterotoxin A (SEA), B (SEE), and toxic shock syndrome toxin 1 (TSST-1) bind to major histocompatibility complex (MH C) class II molecules, they differ in their mode of binding. Signaling induced by these toxins via MHC class II molecules seems to be largel y mediated by their mode of interaction. In the present study, we have demonstrated that contrary to SEA, stimulation of the human monocytic cell line THP-1 with SEE or TSST-1 failed to induce interleukin-1 bet a or tumor necrosis factor-alpha gene expression. Treatment of THP-1 c ells with interferon-gamma increased the level of MHC class II express ion but did not enhance the SEE and TSST-1 response. However, crosslin king of SEE or TSST-1 bound to MHC class II molecules with specific an tibodies leads to cytokine gene expression, indicating that dimerizati on of class II molecules is a requirement for this superantigen-induce d response. The presence of anti-CD40 antibodies in the course of SEE or TSST-1 stimulation overcomes this requirement, indicating that cert ain signal(s) induced via CD40 molecules can replace those induced by dimerization of class II molecules. Pretreatment with anti-lymphocyte functional antigen-1 (LFA-1) antibodies completely inhibited SEA-induc ed response as well as that induced by SEE or TSST-1 in the presence o f CD40 antibodies, supporting the involvement of LFA-1 intercellular a dhesion molecule system in these responses. The entirety of these resu lts demonstrate clearly that dimerization of class II molecules is a p rerequisite for superantigen-induced T cell-independent cytokine gene expression which can be replaced by signaling via CD40 in an LFA-1-dep endent system.