We have identified a novel lysosome-associated membrane glycoprotein localized on chromosome 3q26.3-q27, DC-LAMP, which is homologous to CD68. DC-LAMP mRNA is present only in lymphoid organs and DC. A specific MAb detects the protein exclusively in interdigitating dendritic cells. Expression of DC-LAMP increases progressively during in vitro DC differentiation, but sharply upon activation with LPS, TNFalpha, or CD40L. Confocal microscopy confirmed the lysosomal distribution of the protein. Furthermore, DC-LAMP was found in the MHC class II compartment immediately before the translocation of MHC class II molecules to the cell surface, after which it concentrates into perinuclear lysosomes. This suggests that DC-LAMP might change the lysosome function after the transfer of peptide-MHC class II molecules to the surface of DC.

Interleukin (IL)-12 may be secreted as a bioactive T helper type 1 (Th1) cell–inducing heterodimer, as a monomer, or as an antagonistic homodimer. We analyzed the IL-12 produced by mouse splenic dendritic cells (DCs), human thymic DCs, and cultured human monocyte-derived DCs. IL-12 production required both a microbial or T cell–derived stimulus and an appropriate cytokine milieu. The different IL-12 forms were differentially regulated by the cytokines present rather than the stimulus used. IL-4 alone or together with granulocyte/macrophage colony-stimulating factor or interferon γ effectively enhanced the production of the bioactive heterodimer and selectively reduced the antagonistic homodimer of IL-12. Therefore, IL-4, the major Th2-driving cytokine, provides a negative feedback causing DCs to produce the major Th1-inducing cytokine, bioactive IL-12.

Within T cell–rich areas of secondary lymphoid organs, interdigitating dendritic cells recruit antigen-specific T cells that then induce B cells to secrete Igs. This study investigates the possible role(s) of dendritic cells in the regulation of human B cell responses. In the absence of exogenous cytokines, in vitro generated dendritic cells (referred to as Dendritic Langerhans cells, D-Lc) induced surface IgA expression on ∼10% of CD40-activated naive sIgD+ B cells. In the presence of IL-10 and TGF-β, a combination of cytokines previously identified for its capacity to induce IgA switch, D-Lc strongly potentiated the induction of sIgA on CD40-activated naive B cells from 5% to 40–50%. D-Lc alone did not induce the secretion of IgA by CD40-activated naive B cells, which required further addition of IL-10. Furthermore, D-Lc skewed towards the IgA isotype at the expense of IgG, the Ig production of CD40-activated naive B cells cultured in the presence of IL-10 and TGF-β. Importantly, under these culture conditions, both IgA1 and IgA2 were detected. In the presence of IL-10, secretion of IgA2 by CD40-activated naive B cells could be detected only in response to D-Lc and was further enhanced by TGF-β. Collectively, these results suggest that in addition to activating T cells in the extrafollicular areas of secondary lymphoid organs, human D-Lc also directly modulate T cell–dependent B cell growth and differentiation, by inducing the IgA isotype switch.

In this study, 2 distinct populations of mature dendritic cells (DCs) were identified in the human thymus. The major population is CD11b ؊ , CD11c ؉ , and CD45RO low and does not express myeloidrelated markers. It displays all the characteristics of mature DCs with a typical dendritic morphology, high surface levels of HLA-DR, CD40, CD83, and CD86, and expression of DC-lysosome-associated membrane glycoprotein messenger RNA (mRNA). In addition, CD11b ؊ thymic DCs do not express macrophage inflammatory protein-1␣ (MIP-1␣) mRNA, but express thymus-expressed chemokine (TECK) mRNA and are able to secrete bioactive interleukin 12 (IL-12) upon stimulation. In contrast, the minor and variable thymic DC population is CD11b ؉ , CD11c high , and CD45RO high and comprises CD83 ؉ CD14 ؊ mature and CD83 ؊ CD14 ؉ immature DCs. It expresses macrophage-colony stimulating factor receptor, MIP-1␣ mRNA and high amounts of decysin mRNA after CD40 activation, but does not express TECK and is a weak bioactive IL-12 producer. Also identified were the IL-3R␣ high plasmacytoid cells, which are present in the thymic cortex and medulla. Upon culture with IL-3, granulocyte/macrophage-colony stimulating factor, and CD40 ligand, the plasmacytoid cells can adopt a phenotype resembling that of freshly isolated CD11b ؊ thymic DCs. However, these plasmacytoid-derived DCs fail to secrete bioactive IL-12; therefore, conclusions cannot be made about a direct relation between thymic plasmacytoid cells and CD11b ؊ DCs. Whereas CD11b ؉ thymic DCs appear to be related to tonsillar germinal-center DCs, the major CD11b ؊ IL-12-secreting human thymus DC population has similarities to mouse CD11b ؊ CD8 ؉ DCs. IntroductionDendritic cells (DCs) are professional antigen presenting cells 1 that form a dynamic network throughout most tissues and organs and that are crucial for the immune surveillance of the body. [2][3][4] The current model is that Langerhans cells, immature DCs found in epithelia, are the precursors of mature "interdigitating" DCs, found in the T-cell zones of lymphoid organs. 5 Immature interstitial DCs in various tissues, such as the dermis, move into germinal centers as germinal center DCs (GCDCs). In the lymph nodes, tonsils, and spleen, the mature DCs present the antigen captured in the periphery to naive T cells and induce immunity. The DCs of the thymus have a somewhat different role, namely, to present selfantigens and induce negative selection of potential auto-reactive T-cell clones. 6 Until recently, the interdigitating DCs were considered a single population of mature DCs. However, this laboratory and others showed that distinct DC subsets of different lineage derivation and different functions 7-13 could be distinguished in mouse lymphoid organs. On the one hand, CD8 ϩ DCs, lacking myeloid markers such as CD11b and apparently arising from a lymphoid-committed progenitor, 14 are typically potent interleukin 12 (IL-12)-secreting mature DCs. 10,13,15 CD8 ϩ DCs are present at various levels in all mouse lymphoid organs and constitute...

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SummaryIn the present review, a series of studies on the origins of dendritic cells of mice and humans are summarized. Several subsets of mature dendritic cells found in vivo are described and these may correspond to distinct lineages. There is evidence that some dendritic cells are myeloid-derived and that others are lymphoid-derived. The different ways of generating dendritic cells are examined and an attempt to reconcile the differences seen using mouse and human culture models is made. The particular case of Langerhans cells is discussed and an historical overview of the biology of the plasmacytoid T cells, which may represent a distinct 'lymphoid-related' dendritic cell lineage, is given. It is concluded that three or four different pathways lead to the development of different subtypes of dendritic cells.

The antigen presenting dendritic cells (DC) found in mouse and human lymphoid tissues are heterogeneous. Several subsets of mature DC have been described and these may correspond to distinct lineages. In this review, we present evidence obtained from a series of studies on the lineage origin of DC. This evidence points to the existence of at least three pathways for DC development, namely one from myeloid progenitors, a second from lymphoid progenitors and the third for Langerhans cells from precursors whose relationship to myeloid or lymphoid cell types is not yet clearly defined.

The epidermal growth factor-transmembrane seven (EGF-TM7) family are proteins that express EGF-like domains at their extracellular N-terminus coupled to a classical seven transmembrane (TM7) cassette. Recently, we identified, in mice, a novel member of this family termed FIRE (EMR-4). Here, we present the structure of the mouse and human FIRE genes. The structures of the two genes are strikingly similar, with the positions of the introns, relative to the deduced protein sequences, highly conserved. Moreover, the gene structures are typical of other members of the EGF-TM7 family. Other researchers have identified a point deletion in exon eight of the human FIRE gene, which introduces a frame shift into the cDNA leading to a premature stop codon. Thus, human FIRE is predicted to be expressed only as a soluble protein; even though sequence potentially encoding the TM7 cassette is found in a separate open reading frame of the same mRNA transcript. We explored the possibility that a cell surface expressed form of human FIRE did exist, either as an allelic variant, or as an alternatively spliced transcript. Although, we did identify two alternatively spliced human FIRE transcripts, neither are predicted to express the TM7 cassette. Thus if human FIRE exists, it is likely to be expressed as a soluble secreted molecule.