Classical or myeloid dendritic cells are mononuclear cells derived from bone marrow precursors and closely related to monocytes. There are many subsets, but there are differences between these subsets in mice compared with humans and other primates, particularly in their surface markers. So only those relating to humans are described here, though clearly their corresponding functions have been described in all mammalian species studied so far.
Immature dendritic cells are ubiquitous, particularly in epithelia that serve as a portal of entry for microbes, where they capture antigens as well as reacting to pathogen components quickly, within a few hours of invasion. Subsequently, the activated DCs migrate to draining lymph nodes and mature to present antigen to cells of the adaptive system (Fig. 1).
Fig1. Antigen- presenting cells and their associated sites.
DCs have a range of functions: as well as processing antigens , they are able to recognize and respond to pathogens by secreting IFN- α, produce IL- 12 and chemokines as well as causing the differentiation of immature T cells to a variety of effector T cells. Depending on the environment of the cell, which is not entirely understood, mature DCs can activate CD4+ cells to become Th1, Th2, Th17, CTLs and regulatory T cells (Tregs) or to induce apoptosis and so induce tolerance. Immature and mature DCs have different sets of surface proteins (which act as distinct markers), in keeping with their different functions, depending on whether they are immature (for antigen capture/sensing pathogens via PRRs) or mature (for presentation of antigen to T cells).
The interaction between DCs and T cells is strongly influenced by a group of cell surface molecules that function as co- stimulators: CD80 (also known as B7- 1) and CD86 (B7- 2) on the activated DC, each of which engages with counter receptors on the T- cell surface referred to as CD28 and CTLA- 4. A functional co- stimulatory pathway is essential for T- cell activation. In the absence of a co- stimulatory signal, interaction between DCs and T cells leads to T- cell unresponsiveness (Fig. 2). The importance of the co- stimulatory pathway is underlined by the ability of antagonists to co- stimulatory molecules to interrupt immune responses both in vitro and in vivo. This observation has been exploited therapeutically in mice with advanced lupus, in which treatment with a CTLA- 4 con jugated protein to block CD28 leads to significant improvement in disease activity. Translation to human therapeutic monoclonal antibodies has succeeded despite a rocky start. Abatacept, a CTLA- 4 fusion protein, is licensed for the treatment of rheumatoid arthritis. T- cell activation by DCs also depends on cytokines secreted by activated DCs such as IL- 12.
Fig2. (a, b) Role of co- stimulatory pathway in T- cell activation. APC, antigen- presenting cell; MHC, major histocompatibility complex.
Processed antigen is presented to T cells complexed with the MHC class II antigens on the APC surface, since T cells do not recognize processed antigen alone. The most efficient APCs are the interdigitating dendritic cells found in the T- cell regions of a lymph node (Figs 3 and 2). These dendritic cells have high concentrations of MHC class I and II molecules, co- stimulatory molecules (CD80, CD86) as well as adhesion molecules on their surfaces and limited enzymatic powers, which enable antigen processing but not complete digestion. Being mobile, they are able to capture antigen in the periphery and migrate to secondary lymphoid organs, where they differentiate into mature dendritic cells and interact with naive T cells. These cells are known as Langerhans cells when present in the skin.
Fig3. Receptors and functions of mononuclear phagocytic cells.
These cells differ from the follicular dendritic cells in the follicular germinal centre (B- cell area) of a lymph node (see Figs 3 and 2). Follicular dendritic cells have receptors for complement and immunoglobulin components and their function is to trap immune complexes and to feed them to B cells in the germinal centre. This is part of the secondary immune response, since preexisting antibodies are used, accounting for B- cell memory.
Plasmacytoid DCs are found in blood and mucosal- associated lymphoid tissues and can secrete large quantities of type I IFNs in response to viral infections. However, their precise role and repertoire and therefore clinical significance remain unclear.
The few DCs in the blood are typically identified and enumerated in flow cytometry. Three types of DCs have been defined in human blood and these are the CD11c+ myeloid DCs, the CD141+ myeloid DCs and the CD303+ plasmacytoid DCs (as per the IUIS Nomenclature committee). Dendritic cells in blood are less mature and have no projections from their surface (dendrites). Still, they can perform complex functions, including chemokine production in CD11c + myeloid DCs, cross- presentation of antigen in CD 141+ myeloid DCs and IFN- a production in CD303+ plasmacytoid DCs.
Monocyte- derived DCs, also known as myeloid DCs, are activated (mature) DCs that are found in inflammatory sites, from whence they travel to draining lymph nodes. As with other mature DCs, they express co- stimulatory molecules and so can activate T cells. Under certain circumstances they can even secrete TNF- α and nitric oxide. The ability to culture these cells from human blood monocytes has led to the concept of DC vaccines for cancers.
Activated B cells themselves are also able to present antigen (Fig. 1).
