Besides their classical function in antigen presentation, MHC class I molecules have now been shown to negatively regulate Toll-like receptor (TLR)-triggered inflammatory responses. Xu et al. first noted that MHC class I-deficient mice produced markedly more pro-inflammatory cytokines in response to TLR ligands and were more sensitive to lethal challenge with lipopolysaccharide (LPS) than control mice. Interaction of MHC class I-expressing macrophages with CD8+ T cells led to the suppression of TLR-triggered cytokine production. Further analyses revealed that the intracellular tyrosine residues in membrane MHC class I molecules are phosphorylated by the kinase SRC after LPS stimulation of macrophages, and this allows the recruitment of the kinase FPS to the MHC class I molecules. FPS mediated the suppressive effect by activating the phosphatase SHP2, which interferes with TLR signalling mediated by TNFR-associated factor 6 (TRAF6).