Videos: Genentech (showing phagocytic cells taking in antigens)
Introduction:
The dendritic cell is one of the major means by which innate and adaptive immune systems communicate. It is believed that these cells shape the adpative immune response by the reactions to microbila molecules or signals. Dendritic cells capture, process and present antigens, thus activating CD4+ and C3*+ naive T lymphoctes. leading to the induction of primary immune responses, and derive their stimulatory potency form expression of MHC class I, MHC class II, and accessory molecules, such as CD40, CD54, CD80, CD86, and T-cell activating cyctokines.
DCs are special in terms of their antigen processing machinery. Classically (for non-professional APCs and normal cells) antigens derived form intracellular sources are presented by the MHC class I presentaiton system while extracellular antigens (captured via phagocytosis or pinocytosis) are preferentially procesesd for MHC class II presentation. In specialized APCs like DCs, however, the extracellular antigens can also gain access to the MHC class I presentation system (mediated by the following eventss: phogophore-endosome-antigen escape from endosome-antigen processing by cytosolic proteasome for MHC I presentation) while intracellular antigen fragments can also be found on teh MHC class II molecules (mediated by autophagy), a phenomenon termed as “cross-presentation“. (Dudek, “Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity” frontiers in immunology, 2013).
Based on a highly stark difference between antigenic enviornments (i.e., host “self” antigens vs. foreign or pathogen-assocaited “non-self” antigens, DCs can exist in two main states; steady state immature immature dendritic cells (iDCs) and fully mature DCs. Phenotypic maturation is attained when DCs up-regulate surface maturation ligands such as CD80, CD83 and CD86 along with the MHC II molecule. DCs stimulated on the functional level exhibit the ability to secrete cytokines where the balance between inflammatory or immunostimulatory cytokines (e.g. IL-12, IL-6, IL-1beta) and immunosuppressive cytokness (e.g., IL-10, TGF-beta) is decided by the environmental context. (Dudek, “Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells itnerface that augments anticancer immunity” frontiers in immunology, 2013)
Importance of DC in Self-Tolerance:
A single DC can contact as many of 5k T cells per hour. Steady state iDCs exhibit continous endocytic activity and hence continously present “self” antigens to T cells. In this case, the T cells are not polarized towards an effector state but are rather polarized to facilitate tolerance or immunosuppression. Such immunotolerance is actively induced and maintained through a mixture of immune checkpoint pathways and complete lack of stimulatory signals provided by the DCs. Immune checkpoint pathways are a plethora of inhibitory cascades that are crucial for maintaining self-tolerance and modulation of duration/amplitude of immune resposne (e.g., DC based presetnation of ligands like cytotoxic T-lympocyte-associated antigen 4 (CTLA4) and programed cell death protein 1 (PD1) to T cells causing T cell anergy or differentation of immunosuppressive T cells. Such immnosuppressive T cells (e.g., regulatory T cells Tregs) further help in spreading toelrance twoard “self-antigens”. On the other hand, when DCs encounter pathogens possessing yield suitable antigenic peptides that are subsequently loaded on MHC class I and II molecules for presentation to T and B cells. (Dudek, “Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells itnerface that augments anticancer immunity” frontiers in immunology, 2013)
Dc which switch to a mature state exhibiting strong phenotypic and functional stimulation. At this stage, the DCs leave the function of phagocytic scavenging and assume the more sophisticated APC function. Subsequently, DC carefully co-ordinate their proteolytic processes in the cytosol (e.g., proteasome), endosomes-lysosomes (e.g., lysosomal hydrolases) and the ER to degrade “non-self” entity derived proteins.
Induction of Adaptive Immune Response:
CD8 T cells activation: The induction of an adaptive immune response requires the interation of several lymphoid and myeloid cell types. For the generation of cytotoxic T lymphocytes (CTL), initial activation of naive CD8 T cells occurs via antigen-presenting cells (APC) that engage the antigen–specific T cell receptor (TCR) and other stimulatory surface receptors of these lymphoctes. The critical MHCI molecules involved in TCR recognition by CD8-T cells can be loaded with antigenic determinants by a direct antigen-presentation pathway involving cytosolic proteins or by a cross-presentation pathway, which is fuled by extracellular proteins, which is believed to play an essential role for pathgogens that do not directly infect APC. (Kastenmuller, “Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions” Cell, 162(6), 2015)
CD4 T cell activation: A second conventiional T cell, the CD4+ T helper T cell, activated via antigen-presenting MHCII molecules. In distinction to the ligands involved in activation of CD8+ T cells, antigenic peptides presented by MHCII molecules are typically derived from extracellular proteins or intracellular proteins that are recycled from the cell surface. These CD4+ T cells provide crucial soluble and membrane associated signals to antigen-speciic B lymphoctes, leading to efective adaptive humoral immunity. As with B cells and humoral resposnes, CD4+ T cells also provdie molecule “help” to CTL, optimizing cellular immune respoens by enhancing CD8% cell clonal expansion, differentation and survival. (Kastenmuller, “Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions” Cell, 162(6), 2015).
DC-CD4+ T cell interations lead to the production of the chemokines CCL3/4 that attract CD8+ T cells via CCR5 to the licensed DC optimizing rare cell contacts. (Kastenmuller, “Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions” Cell, 162(6), 2015).
XCR1+ DCs: Initial priming of CD4+ and CD8+ T cells is spatially segregated within the lymph node and occurs on different DC with temporally distinct pattern of antigen-presentation via MHCI vs. MHCII molecules. DC (XCR1+) that co-present antigen via both MHC molecules are detected at a latter state. These XCR1+ DC are the critical platform involved in CD4+ T cell augmentation of CD8+ T cell responses. (Kastenmuller, “Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions” Cell, 162(6), 2015)
Dendritic Cells Subtypes:
It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens.
Plasmacytoid DCs (pDCs): Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4+ T cells. See Abrigani
Plasmacytoid dendritic cells (pDCs) are innate immune cells that produce type I interferon (IFN-I) and other cytokines in response to virus-derived nucleic acids. Plasmacytoid dendritic cells (pDCs) sense virus-derived nucleic acids through Toll-like receptors (TLRs) 7 and 9 and respond with massive IFN-I production. See Reizes
Myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. See Abrigani
In the Lung:
In the lung, DCs perform a range of tasks including recognition and acquisition of antigens derived from pathogens and allergens, antigen transportation to the regional lymph nodes, and perhaps most importantly, induction of CD4+ or CD8+ T cell immunity. In the unperturbed lung, the DC network is composed of several distinct respiratory DC (RDC) subsets that differ in phenotype, anatomic localization, and function. Of these, CD103+ and CD11bhi RDC subsets exhibit several features characteristics of DC found in extralymphoid mucosal sites and are distributed at distinct anatomical sites: primarily intraepithelial localization for CD103+ RDC and submucosal/interstitial distribution for CD11bhi RDC. In addition to these major populations, monocyte-like RDC (Mo-RDC) are also readily detectable in the uninflamed lung. In certain microenvironments within the lung parenchyma (i.e., alveolar septa), so-called conventional RDC (cRDC) (e.g., CD103+ and CD11bhi RDC) and plasmacytoid DC (pDC) are both detectable. The human counterparts of murine CD103+, CD11bhi RDC and pDC have recently been identified in the human lung.
In Mice:
In mice, CD8α+ mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8α− mDCs preferentially prime CD4+ T cells and promote Th2 or Th17 differentiation. BDCA-3+ mDC2 are the human homologue of CD8α+ mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8+ T-cells and to produce IFN-λ. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. See Abrigani