Conventional dendritic cell
Introduction
Conventional dendritic cells (cDCs) are a subset of dendritic cells, which are pivotal in the immune system for their role in antigen presentation and the initiation of the adaptive immune response. These cells are primarily involved in capturing, processing, and presenting antigens to T cells, thereby acting as a bridge between the innate and adaptive immune systems. cDCs are distinct from other dendritic cell subsets, such as plasmacytoid dendritic cells, due to their unique surface markers, developmental pathways, and functional roles.
Development and Differentiation
cDCs originate from hematopoietic stem cells in the bone marrow. The differentiation process involves several stages, beginning with the common myeloid progenitor, which gives rise to the macrophage and dendritic cell progenitor (MDP). The MDP further differentiates into the common dendritic cell progenitor (CDP), which then bifurcates into pre-cDCs and plasmacytoid dendritic cells. Pre-cDCs migrate to peripheral tissues where they mature into cDCs.
The differentiation of cDCs is regulated by various transcription factors, including IRF8, Zbtb46, and Batf3, which are critical for their development and function. The cytokine environment, particularly the presence of Flt3 ligand, also plays a crucial role in the proliferation and differentiation of cDCs.
Subtypes of Conventional Dendritic Cells
cDCs are broadly classified into two main subtypes: cDC1 and cDC2, each with distinct phenotypic markers and functional specializations.
cDC1
cDC1 cells are characterized by the expression of CD8α and CD103 in mice, and CD141 (BDCA-3) in humans. They are particularly efficient in cross-presentation, a process by which extracellular antigens are presented on MHC class I molecules to CD8+ T cells. This ability makes cDC1 crucial for initiating cytotoxic T cell responses against tumors and viral infections. cDC1 development is heavily dependent on the transcription factor Batf3 and the cytokine IL-12, which also enhances their ability to produce interferon-gamma (IFN-γ).
cDC2
cDC2 cells express CD11b and CD1c (BDCA-1) in humans and are adept at presenting antigens on MHC class II molecules to CD4+ T helper cells. They play a significant role in the activation of T helper cell responses and are involved in the regulation of immune responses against extracellular pathogens. The development of cDC2 is regulated by the transcription factor IRF4, and they are known to produce a variety of cytokines, including IL-6 and IL-23, which are important for Th17 cell differentiation.
Functional Roles
Conventional dendritic cells are central to the initiation and regulation of immune responses. Their primary function is to capture antigens through phagocytosis, macropinocytosis, or receptor-mediated endocytosis. Once internalized, antigens are processed and presented on major histocompatibility complex (MHC) molecules to T cells.
cDCs are also involved in the maintenance of immune tolerance. In the absence of inflammatory signals, cDCs can induce tolerance by promoting the differentiation of regulatory T cells (Tregs) or by inducing anergy in autoreactive T cells. This function is crucial in preventing autoimmune diseases and maintaining immune homeostasis.
Interaction with T Cells
The interaction between cDCs and T cells is a highly orchestrated process involving the formation of an immunological synapse. This interaction is mediated by the binding of T cell receptors (TCRs) to peptide-MHC complexes on the surface of cDCs. Co-stimulatory molecules such as CD80 and CD86 on cDCs provide additional signals necessary for T cell activation and proliferation.
cDCs also produce cytokines that influence T cell differentiation. For example, IL-12 produced by cDC1 promotes the differentiation of Th1 cells, while IL-6 and IL-23 from cDC2 favor the development of Th17 cells. This cytokine milieu is critical for shaping the nature of the adaptive immune response.
Role in Disease and Therapeutics
cDCs are implicated in various diseases, including infections, cancer, and autoimmune disorders. Their ability to present antigens and modulate immune responses makes them a target for therapeutic interventions. In cancer, for instance, cDCs can be harnessed to enhance anti-tumor immunity through vaccines that promote their antigen-presenting capabilities.
In autoimmune diseases, strategies to modulate cDC function aim to restore tolerance and prevent aberrant immune responses. Understanding the pathways that regulate cDC function and differentiation is crucial for developing targeted therapies that can modulate immune responses in a disease-specific manner.