gammadelta T cells play an important role in regulating the immune response to stress stimuli; however, the mean by which these innate lymphocytes fulfill this function remains poorly defined. The main subset of human peripheral blood gammadelta T cells responds to nonpeptidic antigens, such as isopentylpyrophosphate (IPP), a metabolite in the mevalonate pathway for both eukaryote and prokaryote cells. IPP-primed gammadelta T cells significantly augment the inflammatory response mediated by monocytes and alphabeta T cells to TSST-1, the staphylococcal superantigen that is the major causative agent of toxic shock syndrome. Here we show that the small pool of activated peripheral gammadelta T cells induces an early upregulation of CD40 on monocytes and the local release of High Mobility Group Box-1 (HMGB-1), the molecule designated as the late mediator of systemic inflammation. This finding provides a new basis for how gammadelta T cells may serve as influential modulators of both endogenous and exogenous stress stimuli.