Dendritic cells (DCs) are recruited from blood into tissues to patrol for foreign antigens. After antigen uptake and processing, DCs migrate to the secondary lymphoid organs to initiate immune responses. We now show that DC-SIGN, a DC-specific C-type lectin, supports tethering and rolling of DC-SIGN-positive cells on the vascular ligand ICAM-2 under shear flow, a prerequisite for emigration from blood. The DC-SIGN-ICAM-2 interaction regulates chemokine-induced transmigration of DCs across both resting and activated endothelium. Thus, DC-SIGN is central to the unusual trafficking capacity of DCs, further supported by the expression of DC-SIGN on precursors in blood and on immature and mature DCs in both peripheral and lymphoid tissues.

To generate the full diversity of antibody heavy-chain genes, hundreds of dispersed germline V segments must undergo recombination following D-J segment joining. Here we report that this process is regulated by the alpha-chain of the receptor for interleukin-7, a cytokine that stimulates B-cell lymphopoiesis. D-J joining occurs normally in immature B lymphocytes from mice lacking the alpha-chain of the interleukin-7 receptor (IL-7Ralpha). But recombination of V segments is progressively impaired as their distance increases upstream of D/J, causing infrequent rearrangement of most V segments, which markedly reduces diversity. This is not simply due to defective cell proliferation or impaired recombinase expression. Rather, germline transcripts from distal, unrearranged V segments, a marker of chromatin changes that precede recombination, are specifically silenced. So too is expression of Pax-5, which binds to heavy-chain locus control elements and normally stimulates recombination, suggesting a mechanism for these effects. Thus ligands of the interleukin-7 receptor deliver an extrinsic signal that targets V segment recombination in the heavy-chain locus by altering the accessibility of DNA substrates to the recombinase. This mechanism augments the recombinational diversity of the primary antibody repertoire.

CD83 is an immunoglobulin (Ig) superfamily member that is upregulated during the maturation of dendritic cells (DCs). It has been widely used as a marker for mature DCs, but its function is still unknown. To approach its potential functional role, we have expressed the extracellular Ig domain of human CD83 (hCD83ext) as a soluble protein. Using this tool we could show that immature as well as mature DCs bind to CD83. Since CD83 binds a ligand also expressed on immature DCs, which do not express CD83, indicates that binding is not a homophilic interaction. In addition we demonstrate that hCD83ext interferes with DC maturation downmodulating the expression of CD80 and CD83, while no phenotypical effects were observed on T cells. Finally, we show that hCD83ext inhibits DC-dependent allogeneic and peptide-specific T cell proliferation in a concentration dependent manner in vitro. This is the first report regarding functional aspects of CD83 and the binding of CD83 to DCs.

Dendritic cells (DCs) are professional APCs of the immune system that play a key role in regulating T cell-based immunity. The capacity of DCs to activate T cells depends on their maturation state as well as their ability to migrate to the T cell areas of draining lymph nodes. In this study, we investigated the effects of DC maturation stimuli on the actin cytoskeleton and β1 integrin-dependent adhesion and migration. Podosomes, specialized adhesion structures found in immature monocyte-derived DCs as well as myeloid DCs, rapidly dissolve in response to maturation stimuli such as TNF-α and PGE2, whereas the TLR agonist LPS induces podosome dissolution only after a long lag time. We demonstrate that LPS-mediated podosome disassembly as well as the onset of high-speed DC migration are dependent on the production of PGs by the DCs. Moreover, both of these processes are inhibited by Ab-induced activation of β1 integrins. Together, these results show that maturation-induced podosome dissolution and loss of α5β1 integrin activity allow human DCs to undergo the transition from an adhesive to a highly migratory phenotype.