Cells of the dendritic family display some unique properties that confer to them the capacity to sensitize naive T cells in vitro and in vivo. In the mouse, two subclasses of dendritic cells (DCs) have been described that differ by their CD8α expression and their localization in lymphoid organs. The physiologic function of both cell populations remains obscure. Studies conducted in vitro have suggested that CD8α+ DCs could play a role in the regulation of immune responses, whereas conventional CD8α− DCs would be more stimulatory. We report here that both subclasses of DCs efficiently prime antigen-specific T cells in vivo, and direct the development of distinct T helper (Th) populations. Antigen-pulsed CD8α+ and CD8α− DCs are separated after overnight culture in recombinant granulocyte/macrophage colony-stimulating factor and injected into the footpads of syngeneic mice. Administration of CD8α− DCs induces a Th2-type response, whereas injection of CD8α+ DCs leads to Th1 differentiation. We further show that interleukin 12 plays a critical role in Th1 development by CD8α+ DCs. These findings suggest that the nature of the DC that presents the antigen to naive T cells may dictate the class selection of the adaptative immune response.

A monoclonal antibody (145-2C11) specific for the murine T3 complex was derived by immunizing Armenian hamsters with a murine cytolytic T-cell clone. The antibody is specific for a 25-kDa protein component (T3-e) of the antigen-specific T-cell receptor. It reacts with all mature T cells and can both activate and inhibit T-cell function. These results identify T3-E as a cell surface protein involved in the transduction of activation signals.Activation of mature T cells is a process that requires both receptor occupancy by foreign antigen in the context of major histocompatibility complex (MHC) proteins and transduction of a transmembrane signal. The specific antigen recognition has been shown to be dependent on a disulfide-linked heterodimer containing two integral membrane glycoprotein chains, a (45-50 kDa) and / (40-44 kDa) (1). The a and /3 chains are encoded by families of genes, giving rise to a polymorphic set of cell membrane receptors clonally expressed on T lymphocytes. Dembic et al. (2) and Saito et al. (34) have demonstrated that transfection and expression of the genes encoding the aB heterodimer results in the acquisition of MHC-restricted antigen recognition, establishing the direct relationship of antigen specificity to aB expression. The second step of T-cell activation (transmembrane signaling) is presently thought to be mediated by an invariant complex of proteins (T3) that by immunoprecipitation has been shown to be noncovalently associated with the af3 heterodimer in the T-cell receptor (TCR) complex (3, 4). The human T3 complex consists of at least three polypeptides, two glycosylated proteins of 25 kDa and 20 kDa (T3-8 and T3-y, respectively) and an endoglycosidase F-insensitive protein of20 kDa (T3-E) (5). The murine T3 structure has been identified as a similar complex of low molecular mass proteins, including T3-8, T3-e, T3-y, and a 16-kDa polypeptide present as a 32-kDa homodimer (T3-t) (6)(7)(8). The role of the T3 proteins in transmembrane signaling is substantiated by the finding that several of the T3 components have a long intracellular polypeptide portion (9-11) that is phosphorylated upon af3 heterodimer occupancy (12). In addition, monoclonal antibodies (mAbs) binding to the human T3-8 molecule can result in a rise in cytoplasmic free calcium (13), metabolism of phosphatidylinositol phosphates (14), T-cell proliferation (15), lymphokine production (16), and cytolysis (17,18). Recently, mAbs to T3 have allowed the identification of a subpopulation of human T cells that express T3 but not the a,8 heterodimer (19,20). In these cells, the T3 components are associated on the cell surface with polypeptides other than a and 83, including one that appears to be the product of the y gene (19). Anti-T3 mAbs have been shown to activate this T-cell subset, indicating that T3 might also be involved in the signaling of activation signals initiated by the recently described TCRY receptor complex (20).Unlike the study of human systems, the study of murine T-cell activation and ontogeny...

SummaryDendritic cells (DC) are described as "nature's adjuvant," since they have the capacity to sensitize T cells in vivo upon first encounter with the antigen. The potent accessory properties of DC appear to develop sequentially. In particular, the ability to process antigens and to sensitize naive T cells develops in sequence, a process termed "maturation" that is well described in vitro. Here, we obtain evidence for maturation in vivo in response to the bacterial product lipopolysaccharide (LPS). Before LPS treatment, many DC are found at the margin between the red and white pulp. These cells lack the M342 and DEC-205 markers, but process soluble proteins effectively. 6 h after LPS, DC with the M342 and DEC-205 markers are found in increased numbers in the T cell areas. These cells have a reduced capacity to process proteins, but show increases in the B7 costimulator and T cell stimulatory capacity. 48 h after LPS, the number of DC in the spleen is reduced markedly. We interpret these findings to mean that LPS can cause DC in the marginal zone to mature and to migrate into and then out of the T cell areas.

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The main function of dendritic cells (DC) is to induce the differentiation of naive T lymphocytes into helper cells producing a large array of lymphokines, including interleukin (IL)-2; interferon-gamma (IFN-gamma), IL-4, IL-5 and IL-10. The potent immunostimulatory properties of DC develop during a process of maturation that occurs spontaneously in vitro. Since IL-10 has been shown to inhibit Th1 responses, we determined its effect on DC maturation and accessory function. Our data show that DC that have undergone maturation in vitro in the presence of IL-10, have an impaired capacity to induce a Th1-type response in vivo, leading to the development of Th2 lymphocytes. Their inability to promote the synthesis of IFN-gamma seems to correlate with a decreased production of IL-12, an heterodimeric cytokine necessary for optimal generation of Th1-type cells. These results suggest that IL-10 skews the Th1/Th2 balance to Th2 in vivo by selectively blocking IL-12 synthesis by the antigen-presenting cells that play a role of adjuvant of the primary immune response. The cytokines present in the environment at the presentation step may, therefore, determine the class of the immune response induced by DC in vivo, i.e. Th0, Th1 and/or Th2.

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Uncontrolled TNF-α synthesis is known to play an important role in numerous inflammatory disorders, and multiple transcriptional and post-transcriptional regulatory mechanisms have therefore evolved to dampen the production of this important pro-inflammatory cytokine. By examining the anti-inflammatory properties of the vitamin B3 constituent nicotinamide, we have uncovered a novel regulatory pathway controlling TNF-α production. Exogenous nicotinamide inhibits TNF-α secretion through modulation of mRNA translation efficiency. Moreover, the capacity to produce TNF-α appears to be directly correlated with intracellular NAD levels, suggesting that a NAD-dependent biological event that can be inhibited by nicotinamide controls TNF-α synthesis in cells of the immune system. Sirtuins represent NAD-dependent deacetylases involved in regulation of gene expression in both mammals and yeasts, and are known to be inhibited by nicotinamide. We demonstrate herein that similarly to nicotinamide, structurally unrelated sirtuin inhibitors downregulate TNF-α secretion with minimal effect on TNF-α gene transcription. By over-expressing individual sirtuin members in cell lines transiently expressing TNF-α, we have identified SIRT6 as a sirtuin member able to upregulate TNF-α synthesis in vitro. In agreement with this finding, bone-marrow derived dendritic cells from SIRT6 KO mice display reduced TNF-α synthesis in response to CpG. Collectively, these data delineate a novel relationship between metabolism and the inflammatory response, by uncovering the role of SIRT6 in the control of TNF-α secretion.