Dendritic cells (DCs) are amongst the earliest identified accessory/nonlymphoid immune cells; they were described in 1973 by Ralph Steinman and Zanvil Cohn as the immune system’s most powerful antigen-presenting cells (APCs) (Sabado et al., 2017). As APCs, their main role is to locate and process antigen, and dis play antigenic peptides on human leukocyte antigen (HLA) proteins [now referred to as major histocompatibility complex (MHC) molecules], which are present on cellular surfaces. The displayed antigenic peptides are recognized by T cells, which culminates in diverse immunological responses (Steinman, 2012), and thus DCs serve as a link between the adaptive and innate immune systems. They also secrete cytokines and growth factors that control the function of diverse immune cells (O’Keeffe et al., 2015), and in particular maintain a balance between inflammatory and tolerogenic T cell responses (Simones et al., 2010). Originating in the bone marrow, DCs differentiate into cells predominantly found in mucosa, skin, and lymphoid tissues.

DCs play a crucial role in a variety of diseases including cancer, hypersensitivity responses, respiratory diseases, infection, and autoimmunity. Antigen recognition of MHC-II peptide epitopes by naïve CD4⁺ cells results in differentiation into Th1, Th2, and Th17 effector cells  (Nakano et al., 2009; Yamane & Paul, 2013). In skin hypersensitivity, CD4⁺ and CD8⁺ T lymphocytes are activated, leading to secretion of cytokines, and inflammation mediated in part by chemotaxis, resulting in infiltration of more immune cells (Kaplan et al., 2012; Yazdi et al., 2016). In respiratory diseases such as asthma, DCs capture allergens within the airways, leading to a Th2 response, resulting in inflammation of the airway. DCs are also involved in other lung-related inflammatory diseases (Upham & Hughes, 2006)

DCs can induce and modulate immunological tolerance in addition to stimulating the immune system. For example, an in vivo animal study demonstrated that depletion of DCs (by targeting a DC transcription factor engineered to express diphtheria toxin receptor) leads to lympho-angiogenesis and myeloproliferative disorders, emphasizing the role of DCs in maintaining immune tolerance (Meredith et al., 2012). Central tolerance depends predominantly on thymic DCs displaying self-antigens to T cells. Thymic DCs delete auto-reactive lymphocytes by negative selection, and positively select regulatory T cells (Treg) for the maintenance of immunological tolerance toward self antigens. Thymic DCs that play major roles in central tolerance include migratory DCs (CD8α- CD11b⁺1SIRPα⁺), resident DCs (CD8α⁺SIRPα^-), and plasmacytoid DCs (pDCs; CD11c^intCD45RA^int) (Audiger et al., 2017; Cools et al., 2007; Hilkens et al., 2010).

DCs have been employed to induce cytotoxic T lymphocyte (CTL)-mediated immune responses against tumor cells in cancer immunotherapy (Lee & Radford, 2019), and DC cancer vaccines have been developed as personalized cancer therapy (Perez, & De Palma, 2019). DCs not only stimulate CD8⁺ T lymphocytes to produce apoptosis-inducing responses, but also trigger NK cells to release perforins and granzymes capable of killing tumor cells (Castell-Rodr´ıguez et al., 2017).

DCs are found in two forms: mature and immature. Immature DCs (iDCs) recognize disease-causing organisms using pattern recognition receptors (PRRs); these PRRs recognize damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) on pathogen surfaces (Hemmi & Akira, 2005), leading to phagocytosis and lysosomal digestion. Maturation of DCs is then initiated, and DCs move into lymph nodes to deliver antigen to naive T cells (Mbongue et al., 2017). Mature (mDCs) and iDCs upregulate costimulatory proteins (CD40, CD80, CD86, and CD83) that help to stimulate T cells, and CCR7, a chemotactic receptor that encourages homing of lymphocytes and DCs to lymph nodes. The DC maturation process is an important process in vaccine development, as mDCs are capable of eliciting strong immune responses.

In addition to antigen presentation on MHC-II molecules, which is necessary for the activation of CD4 T cells, DCs can activate CD8 cytotoxic T cells (CTL) via a process known as cross-presentation or cross-priming. In this process, antigens or pathogens that have undergone phagocytosis are processed in endosomes and resulting peptide fragments are loaded onto Class I MHC rather than Class II. This is an important mechanism in vaccine-induced immunity for cancer, and intracellular pathogens, which are targeted by CTL.

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