The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction. at a very low rate under physiological steady-state conditions without replenishment by blood-borne precursors (33, 34). Recent early-phase studies of DCregs have begun to examine the security and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction. at a very low rate under physiological steady-state conditions without replenishment by blood-borne precursors (33, 34). In contrast to cDCs, LC development is L-2-Hydroxyglutaric acid impartial of FMS-like tyrosine kinase 3(Flt3) and Flt3 ligand (Flt3L) but requires colony-stimulating factor 1 receptor (Csf-1R) like many tissue-resident macrophages, such as microglial cells and Kupffer cells (35, 36). Recently, IL-34 has been identified as the second functional ligand for Csf-1R L-2-Hydroxyglutaric acid and was required for the development of LCs and microglial cells (37). In the current classification of DCs, it is unclear whether DCregs constitute an independent DC subset or represent a specific functional state of DCs. In fact, most DC subsets can exert regulatory function through L-2-Hydroxyglutaric acid T cell anergy, T cell deletion, and Treg induction (38, 39). The lifespan of DCs is generally short, and continuous replenishment from bone marrow progenitors is essential to maintaining DC homeostasis (40). Except for LCs, the majority of DC subsets originate from the same progenitors, namely monocyte-macrophage DC progenitors (MDPs), which reside in the bone marrow (19, 41) (Physique 1). MDPs further give rise to common monocyte progenitors (cMoPs) and common DC progenitors (CDPs) (42, 43). cMoPs develop into blood monocytes in the bone marrow but further differentiate into MoDCs in tissue as a consequence of inflammation or contamination (29, 43C46). CDPs further give rise to pDCs and pre-DCs (47, 48). pDCs terminally differentiate into fully developed cells in the bone marrow, then migrate out to patrol the blood and peripheral organs (49, 50). Pre-DCs migrate out of the bone marrow through the blood to seed non-lymphoid and lymphoid organs, where they terminally differentiate into cDCs (36, 51, 52). LCs derive predominantly from embryonic fetal liver monocytes with a minor contribution from yolk sac-derived macrophages and are managed locally by self-renewal under steady-state conditions (33, 53). In severe inflammatory conditions, LCs are replaced by blood-borne monocytes and acquire the capacity for self-renewal (35, 54). Open in a separate windows Physique 1 Origin and development of dendritic cells. With the exception of LCs, DCs develop from bone marrow-derived precursors. CDPs give rise to cDCs and pDCs. Monocytes differentiate into MoDCs in tissue as a consequence of inflammation or contamination. LCs originate in prenatal precursor cells and are managed locally by self-renewal under steady-state conditions. While under a severe inflammatory condition, LCs are replaced by blood-borne monocytes and acquire the capacity of self-renewal. DC, dendritic cell; LC, langerhans cells; CDP, common dendritic cell progenitor; cDC, classical dendritic cell; pDC, plasmacytoid dendritic cell; MoDC, monocyte-derived dendritic cell; YS-EMPs, Yolk sac-derived erythromyeloid progenitor cells; P-Sp/AGM para-aortic splanchnopleure/aorta, gonads, and mesonephros; HSC, hematopoietic stem cells; CMP, common myeloid progenitor cell; MP, myeloid progenitor cell; cMoP, common monocyte progenitor; GMP, granulocyte-macrophage progenitor; MDP, monocyte-macrophage DC progenitor. Function of DCs in Transplantation DCs are crucial to linking the innate and adaptive response in transplantation, in other L-2-Hydroxyglutaric acid words, to initiating strong, donor-specific, L-2-Hydroxyglutaric acid alloreactive T cell activation. During a classical immune response, immature DCs sense the presence of damage- and pathogen-associated molecular patterns (DAMPs and PAMPs), the so-called Transmission 0s, from damaged cells and microbial CDKN1C molecules, respectively, via pattern acknowledgement receptors (PRRs) (55, 56). These PRRs mediate internalized antigens and their routing to antigen-processing pathways (57). Subsequently, PRRs activate a series of intracellular pro-inflammatory molecular signaling cascades, such as interferon-responsive factor and nuclear factor kappa B pathways (58, 59). Activation of these signaling pathways prospects to maturation of DCs, characterized by upregulation of MHC molecules, costimulatory molecules (e.g., CD80, CD86), chemokine receptors (e.g., C-C chemokine receptor type 7, CCR7), adhesion molecules (e.g., CD62L), and pro-inflammatory cytokines (e.g., TNF-, IL-12) (60C62). Chemokine receptors and adhesion molecules permit DCs to migrate to lymphoid organs, where they contact and primary T cells (63C65). Antigens loaded on MHC class I molecules are offered to CD8+ T cells, whereas antigens loaded on MHC class II molecules are offered to CD4+ T cells. Costimulatory molecules and pro-inflammatory cytokines provide the.