At specific anatomical sites (thymus) DC exert tolerogenic functions despite being in a potentially inflammatory environment. all, we would like to arouse fascination for this cell type and its therapeutic potential in skin diseases. in murine bone marrow precursors lead to a drastic reduction of pDC and and are substantial in the maintenance of LC homeostasis. In addition to phenotypic/functional classifications, DC classify by their Flucytosine migratory capabilities and differentiation stage. Attempts have been made to distinguish resident DC from migrating DC based on markers. For example, resident DC (pDC or cDC subgroups such as CD8+ DC or CD8-/CD11b+ DC) in lymphoid organs (12) or migrating DC from peripheral tissues and non-lymphoid organs (including CD103+/Langerin+/CD11b+) can be distinguished Rabbit Polyclonal to ATRIP (13). However, however, all DC migrate both in steady state and in inflammation. In the blood, a population of pre-DC forms a subset that is functionally distinct from pDCs and cDCs. AXL and Siglec6 (CD327) expressing cells (AS DC) strongly stimulate T cells in lymphoid tissue. AS DC may also represent a mature cDC2 progenitor and are likely in transition to this subgroup (3). The description of immature (iDC) and mature (mDC) phenotypes primarily refers to the maturation of DC are similarly altered. Key Questions and Future Directions for the Field The increasing use of scRNA-seq has led to the description of additional DC subtypes. Transcriptomes, however, incompletely reflect the cell state as gene transcription is stochastic, characterized by transcriptional bursts of varying intensity (15) and half-lives of individual mRNA molecules vary considerably (16). Therefore, there is a need to determine whether the putative heterogeneity of DC, as evidenced by scRNA-seq, also reflects functional differences. Dendritic Cell Functions DC are versatile cells that act as sensors for pathogens and gatekeepers of tolerance at the same time. They link innate signals (pattern recognition and early inflammatory mediators) to adaptive immune responses (T cell priming and Treg induction). DC functions are diverse and highly dependent on circumstances such as cytokines, tissue and cell origin. DC properties, including surface molecules and secreted soluble mediators, can result in tolerogenic as well as stimulatory effects. This means that their function can be beneficial in relation to peripheral tolerance induction or disadvantageous as in transplant rejection (17). DC decide on the quality and quantity of the immune response simply by their degree of activation ( Figure?2 ). As professional antigen-presenting dendritic cells (APCs), they take antigens from their environment, process them and provide co-stimulation that can prime na?ve T cells unlike any other MHCII-carrying cell in the body. Open in a separate window Figure?2 targeting Flucytosine of DC for Treg induction. Systemic administration of specifically designed nanoparticles or antibodies combined with antigen delivery for tolerogenic DC targeting toll-like receptors (TLR), C-type lectins or RIG-I-like receptors or sensing of inflammatory cytokines such as tumor necrosis factor (TNF) alpha, interleukins 1 and 6 cytokine receptors (18) induces a differentiation program in DC that has been termed mature (18). Such mature DC then express costimulatory molecules, MHC-II Flucytosine and chemokine receptors, which facilitate migration to the lymphoid organs and secretion of elevated levels of inflammatory cytokines. It must be noted, however, that although a DC exhibits characteristics that are termed mature, it may have non-immunogenic functions such as tolerance maintenance. At specific anatomical sites (thymus) DC exert tolerogenic functions despite being in a potentially inflammatory environment. Interesting in this regard is the NF-B pathway. NF-B is known as a target gene of TNF- signalling but can also induce TNF- expression during DC maturation. Earlier reports suggest that NF-B1 is involved in the repression of TNF- expression in immature DCs by itself (19, 20). Steady-state DC actively induce a tolerance-promoting state (regulatory T-cell (Treg) induction) or render T-cells unresponsive (anergy) (21). Tolerogenic maturation has been shown to depend on IRF4, and ablation of IRF4 in DC impairs peripheral tolerance induction Flucytosine (22, 23) ( Figure?1 ). Open in a separate window Figure?1 Dendritic cells exhibit immunostimulatory or tolerogenic potential depending on the context. DC’s fate depends on cytokines and pathogen contact. Inflammatory cytokines and pathogens presenting TLR ligands promote T effector cells, while anti-inflammatory cytokines or interactions with commensal bacterial components produce tolerance, e.g. induce T cell anergy or deletion, or give rise to regulatory T cells. Interestingly, human tolerogenic DC (IL10-DC) matured in the presence of interleukin-10 induce functional regulatory T-cells regardless of their degree of maturation (CD83 low and high) (24, 25). In addition, DC express distinct toll-like receptors (TLRs), which supports their functional specialization, a process that is highly context- and thus cytokine-dependent. A tolerance-promoting function IL-10 has been reported for (26, 27). Because of its barrier function, the skin also harbours commensal bacteria, which colonize the barrier and thus protect the body from.