Some mammalian species show an ability to discriminate between different lipopolysaccharide (LPS) partial structures (for example, lipid A and its congener LA-14-PP, which lacks secondary acyl chains), whereas others do not. Using a novel genetic complementation system involving the transduction of immortalized macrophages from genetically unresponsive C3H͞HeJ mice, we now have shown that the species-dependent discrimination between intact LPS and tetra-acyl LPS partial structures is fully attributable to the species origin of Toll-like receptor 4 (Tlr4), an essential membranespanning component of the mammalian LPS sensor. Because Tlr4 interprets the chemical structure of an LPS molecule, we conclude that LPS must achieve close physical proximity with Tlr4 in the course of signal transduction.endotoxin ͉ macrophage ͉ C3H͞HeJ ͉ specificity

Here, we show that bacteria induce de novo synthesis of both major histocompatability complex (MHC) class I and II molecules in a mouse dendritic cell culture system. The neo-biosynthesis of MHC class I molecules is delayed as compared with that of MHC class II. Furthermore, bacteria stabilize MHC class I molecules by a 3-fold increase of their half-life. This has important consequences for the capacity of dendritic cells to present bacterial antigens in the draining lymph nodes. In addition, a model antigen, ovalbumin, expressed on the surface of recombinant Streptococcus gordonii is processed and presented on MHC class I molecules. This presentation is 10 6 times more efficient than that of soluble OVA protein. This exogenous pathway of MHC class I presentation is transporter associated with antigen processing (TAP)-dependent, indicating that there is a transport from phagolysosome to cytosol in dendritic cells. Thus, bacteria are shown to be a potentially useful mean for the correct delivery of exogenous antigens to be presented efficiently on MHC class I molecules.

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Dendritic cell (DC) maturation is a complex process involving many cell functions. We have studied how the exposure of DC to corticosteroids at different stages of DC maturation affects priming and the expansion of different subsets of CD4+ T cells. Growth factor‐ dependent DC lines and fresh bone marrow‐derived DC were used. When exposed to inflammatory stimuli, immature DC previously treated with dexamethasone were unable to undergo full maturation and were unable to prime Th1 cells efficiently. There was specific and significant reduction in the number of IFN‐γ‐producing effector cell (shown by intracellular cytokine staining) and also in the amount of IFN‐γ produced. Interestingly, the number of IL‐4‐producing T cells and the amount of IL‐4 synthesis was not significantly altered. Furthermore, multiple restimulation of T cells with these DC gave rise to a subpopulation of T regulatory cells (Tr1) which were negative for IFN‐γ and IL‐4 but were IL‐10 positive. In contrast, when DC were activated with lipopolysaccharide prior to dexamethasone treatment, the suppressive effect of glucocorticoids was not significant. Thus, the stage of DC maturation influences the inhibitory effect of corticosteroids. By arresting DC maturation, corticosteroids strongly reduce cell‐mediated Th1 responses and allow the selective expansion of Tr1 cells.