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Dendritic Cell Immunobiology

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DCs link innate and aquired immunity

Dendritic cells (DCs), the most potent antigen (Ag)-presenting cells (APCs), are defined by their dendritic morphology and unique phenotype, and consist of heterogeneous subsets with myeloid- or lymphoid-lineage as well as differing maturity in both lymphoid and peripheral tissues. Immature DCs (iDCs) sense the presence of invading pathogens via various pattern-recognition receptors (PRRs) and process the pathogens intracellularly in inflammatory tissues, and they develop into mature DCs (mDCs) in inflammatory microenvironments. This maturatuin process is associated with upregulation of major histocompatibility complex (MHC) and costimulatory molecules, and downregulation of endocytosis activity and upregulation of Ag-processing ability. In addition, they lose responsiveness to inflammatory chemokines (CCL3 and CCL5,etc.) due to the downregulation of CCR1 and CCR5, and they in turn aquire the responsiveness to homeostatic chemokines (CCL19 and CCL21) via the induction of CCR7. Subsequently, mDCs home into secondary lymphoid tissues where they present the processed Ags to naive T cells to effectively generate type 1 helper T (TH1) cells and TH2 cells, depending on their lineage and activation signals. In addition, mDCs produce various sets of cytokines activating innate immune cells. Thereby, DCs play a crucial role in linking between innate and adaptive immunity.

DCs are regulator of immune response

Accumulating evidence suggest that iDCs are involved in the induction of peripheral tolerance mediated through the induction of T-cell deletion as well as anergic and regulatory T (TR) cells under steady state conditions in vivo. On the other hand, the modification of iDCs with certain immunosuppressive molecules generate tolerogenic DCs, including interleukin (IL-10), active vitamine D3, NFkB inhibitors and vasoactive intestinal peptide (VIP),and they not only show the reduced T-cell stimulatory capacity but also induce anergic T cells and regulatory T (TR) cells in vivo and in vitro. In addition, mDCs expressing inducible costimulator signaling ligand (ICOSL) or indoleamine 2,3 dioxygenase (IDO) exerts regulatory function via induction of T-cell apotosis or TR cells, respectively.Therefore, in addition to the application of mDCs for the therapy of cancer and infectious diseases, strategies utilizing immunoregulatory DCs are expected to be effective for the prevention and treatment of autoimmune diseases, allergic diseases, and allograft rejection. However, the clinical application of normal iDCs and the previous known tolerogenic DCs may not be suitable for the treatment of immunopathogenic diseases, because they likely change into mature under inflammatory condition. Therefore, further development of DCs with a potent negative regulatory ability for T cells is thought to facilitate their use for treatment or prevention of immunopathogenic diseases. We have established human and murine modified DCs with more potent capacity to induce anergic T cells and TR cells than the previously known tolerogenic DCs even under inflammatory conditionin vivo and in vitro, and we therefore designated them as regulatory DCs (DCreg). Our team studies: (1) the clarification of the molecular mechanisms underlying the T-cell regulatory function of DCreg,: (2) the development of immunotherapy with DCreg for immunopathogenic diseases, and to: (3) the characterizion of the specific DC subsets involved in immune regulation.