DCs are “antigen-presenting cells.” An antigen-presenting cell is any cell that uses its major histocompatibility complex (MHC) products (or other antigen-presenting molecules, such as the CD1 molecules that present glycolipids and lipoglycans) to bind and display (i.e., “present”) fragments of antigen to lymphocytes. DCs are more specialized or professional than other antigen-presenting cells. This is because DCs have efficient and regulated pathways for antigen uptake and processing, and DCs possess dozens of features that allow them to initiate and control immunity (Table 21–2). For example, when DCs mature in response to infection, hundreds, even thousands, of gene transcripts can be upregulated or downregulated.17,18
Table 21–2.Important Components of Dendritic Cell Function ||Download (.pdf) Table 21–2. Important Components of Dendritic Cell Function
|Cell processes or dendrites and motility: numerous and continually probing |
|Antigen handling: specialized antigen uptake receptors and processing pathways for classic (MHC) and nonclassic (CD1 and others) presenting molecules, including cross-presentation onto MHC class I and CD1 |
|MHC class II products: high and regulated expression |
|Migration in lymphatics to lymphoid organs and localization to T-cell areas |
|Environmental sensing: multiple receptors for microbial and nonmicrobial products and exaggerated responses to the products |
|Cytokine receptors, including hematopoietins (flt3L and granulocyte-macrophage colony-stimulating factor, but not monocyte colony-stimulating factor, granulocyte colony-stimulating factor) |
|Chemokine receptors, especially for homing to tissues (CCR6) and lymph nodes (CCR7, CCR2) |
|Induction of peripheral tolerance via intrinsic and extrinsic pathways |
|Activation of innate lymphocytes (e.g., natural killer cells) |
ANTIGEN UPTAKE AND PROCESSING
DCs express a wide array of endocytic receptors, which enhance the efficiency of antigen capture, processing, and presentation. Many endocytic receptors are predicted to be C-type lectins, and in some cases their natural ligands have not been identified. DCs also express Fcγ and Fcε receptors, which recognize immune complexes, as well as scavenger receptors. Recognition of pathogens by DC receptors can have two outcomes. One outcome is immune activation followed by antigen presentation and development of a productive immune responses. Alternatively, pathogens may use DC receptors to evade the host immune response. For example, DC-SIGN (CD209) a lectin expressed on DCs, is used by HIV-1 and cytomegalovirus (CMV) to reach T cells and endothelial cells, respectively19,20; by Dengue virus to replicate within DCs21; and by Mycobacterium tuberculosis to trigger production of the suppressive cytokine IL-10.22
Following uptake, efficient processing of antigen yields peptides that bind to MHC class II and class I products. “Exogenous” antigens refer to molecules processed directly following uptake, whereas “endogenous” antigens are processed following biosynthesis in the antigen-presenting cell. Classic pathways of antigen presentation emphasize processing of “exogenous” antigens for presentation on MHC II–peptide complexes to CD4+ T lymphocytes, whereas “endogenous” antigens were targeted for presentation on MHC class I–peptide complexes to CD8+ T cells. However, it is now clear that there is significant overlap in these pathways such that exogenous antigens may also be presented on MHC I products to CD8+ T cells. This pathway is termed cross-presentation and is important for initiation of antitumor immune responses. Cross-presentation is well developed in DCs, especially those found in lymphoid tissues, and leads to either tolerance or activation of CD8+ T lymphocytes, depending upon the DC maturation stimulus.23 For instance, products of dying cells, from transplants, tumors, foci of infection, and self-tissues are endocytosed by DCs then presented on MHC Class I to CD8+ cells.24,25 Importantly, cross-presentation of antigens onto MHC class I can involve the proteasome and transporters for antigenic peptides, which are used in the presentation of endogenous antigens.
DCs are a major cell type involved in cross-presentation of proteins,26,27 and probably of lipids.28,29 Cross-presentation has been documented involving nonreplicating microbes, dying cells, ligands for the DEC205 receptor, and immune complexes, including antibody-coated tumor cells. This pathway allows DCs to induce tolerance or immunity to antigens not synthesized de novo in these cells. Fcγ receptors, in addition to mediating presentation, can influence DC maturation, either enhancing maturation through activating forms of the receptor or preventing maturation through inhibitory forms.30 Such consequences of antibody binding to DC Fc receptors, with regard to DC maturation and cross-presentation, are important features for consideration when trying to understand the use of antibodies as therapeutic agents.
Some DCs subsets also express the CD1 family of antigen-presenting molecules. For example, CD1a typically is found on epidermal Langerhans cells in skin, whereas CD1b and CD1c are expressed on dermal DCs. CD1 molecules present glycolipids, whereas microbial glycolipids are the best studied to date with regard to CD1a, CD1b, and CD1c. CD1d molecules on DCs also efficiently present the synthetic glycolipid α-galactosylceramide.31 This process leads to activation of distinct lymphocytes with a restricted T-cell repertoire, the NKT cells.32 NKT cells have significant potential as effector cells because they can produce large amounts of interferon-γ and lyse tumor targets.
A newer “nonclassical” pathway for antigen presentation involves presentation of “endogenous” proteins on MHC class II.33 This pathway involves autophagy and is also well developed in DCs.34 It allows nuclear, mitochondrial and cytoplasmic proteins to be presented from digestive compartments, including as a first example, the Epstein-Barr nuclear antigen 1.35
MATURATION OF DENDRITIC CELLS
Immature DCs efficiently take up antigen but do not induce immunity, defined as the production of immune effectors and the establishment of memory. For immune induction to occur, DCs require additional stimuli that lead to an intricate differentiation process called “maturation.” Maturation involves changes in endocytic and antigen processing machineries, production of chemokines and cytokines, and expression of many cell-surface molecules, including those of the B7, TNF, and Notch ligand families. DCs have an endocytic system that is tightly regulated and devoted to presentation of captured antigens, rather than clearance and scavenging.
In the case of DCs derived from marrow and monocyte precursors, DC maturation is accompanied by exquisite changes in the endocytic system with attendant consequences for antigen processing and presentation. During maturation, antigen uptake is dampened as a result of inactivation of a rho-guanosine triphosphatase termed cdc42.36 At the same time, machinery associated with antigen processing is augmented. Lysosomal processing is activated by assembly of an active proton pump, which acidifies the lysosome so that processing of antigens and the MHC class II associated invariant chain can proceed. MHC–peptide complexes form within the endocytic system of the maturing DCs,37,38 then traffic in distinct nonlysosomal compartments to the cell surface. Internalization and degradation of MHC II also occurs via ubiquitination is also inhibited in mature DCs.39 DC maturation also increases presentation on MHC I via, in part, the formation of an “immunoproteasome,” a combinatorial form of proteasome that increases the spectrum of peptides destined to be presented on MHC I.40
A hallmark of DC maturation in response to several stimuli is upregulation of costimulatory molecules such as CD80 and CD86, resulting at least in part from production of inflammatory cytokines, particularly TNF-α.32 Importantly however, CD86 upregulation should not be equated directly with immune activation, which requires other DC functions, such as those triggered by CD40 ligation, including production of cytokines such as IL-12 or type I interferons, and/or engagement of other receptors such as CD70.32
DCs enhance antibody formation by several mechanisms. The classical pathway involves induction of antigen-specific CD4+ helper T cells, which then help B-cell growth and antibody secretion. However, DCs can also directly affect B cells to enhance immunoglobulin (Ig) secretion and isotype switching, including production of the IgA class of antibodies, which contribute to mucosal immunity.41,42 DCs can induce a B-cell class switch in a CD40-independent manner, through production of ligands such as B-lymphocyte stimulator (B-cell activating factor belonging to the TNF family [BAFF]) and a proliferation-induced ligand (APRIL), including T-cell–independent induction of IgA antibodies to commensal organisms.43 Plasmacytoid DCs stimulate antibody responses to influenza virus in culture.44 Production of antibodies by any of these mechanisms may lead to interaction with DC FcγR and thereby an adaptive response by T cells.