t cells downregulate macrophage tnf production by irak1mediated il10 expression and control innate hyperinflammation endotoxemia is caused by excessive inflammation but the immune system has various mechanisms to avoid collateral organ damage in endotoxemia a handful of reports have shown that innate immune responses are suppressed by the adaptive immune system however the molecular mechanism by which adaptive immune cells suppress innate inflammatory responses is not clear here we report that t cells are shown to interact with macrophages at the early stage of enodotoxemia and to prolong survival of mice through controlling tnf and il10 levels by macrophage cd40 stimulation the crosstalk between cd40 and tolllike receptor tlr4 signaling first mediates il1 receptorassociated kinase 1 irak1 nuclear translocation and its binding to the il10 gene promoter in macrophages without interfering with the nfb pathway il10 is then detected by macrophages in an autocrine fashion to destabilize tnfa mrna to induce irak1mediated il10 expression signals from both cd40 and tlr4 are essential cd40 signaling induces irak1 sumoylation in the presence of tnf receptorassociated factor 2 traf2 and intracellular isoform of osteopontin iopn whereas tlr4 signaling provides ifn regulatory factor 5 irf5 as a chaperone for sumoylated irak1 nuclear translocation interaction of t cells with macrophages was observed in the spleen in vivo after endotoxemia induction with lps injection our study demonstrates a mechanistic basis for the immunosuppressive role of macrophage cd40 in lps endotoxemia