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308 Part IV: Molecular and Cellular Hematology Chapter 21: Dendritic Cells and Adaptive Immunity 309

CD1c. CD1d molecules on DCs also efficiently present the synthetic DENDRITIC CELL SUBSETS
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glycolipid α-galactosylceramide. This process leads to activation of
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distinct lymphocytes with a restricted T-cell repertoire, the NKT cells. The primary function of DCs is to survey host tissues and initiate
NKT cells have significant potential as effector cells because they can responses upon encountering danger signals. To optimally perform
produce large amounts of interferon-γ and lyse tumor targets. these functions, DCs are present in every tissue of the body, and are
A newer “nonclassical” pathway for antigen presentation involves enriched in lymphoid tissues. Immature DCs are strategically posi-
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presentation of “endogenous” proteins on MHC class II. This path- tioned along body surfaces (skin, airway, gut) and in the interstitial
way involves autophagy and is also well developed in DCs. It allows spaces of many organs, such as the heart and kidneys. DCs are able to
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nuclear, mitochondrial and cytoplasmic proteins to be presented from extend their processes through the tight junctions in epithelia, without
digestive compartments, including as a first example, the Epstein-Barr altering the epithelial barrier, allowing them to sample antigens from
nuclear antigen 1. 35 harmless environmental antigens and commensal microorganisms. In
the steady state, DCs migrate continuously from tissues into afferent
lymphatics and probably blood. By electron microscopy, DCs in lym-
MATURATION OF DENDRITIC CELLS phoid tissues often are termed interdigitating cells, appearing as large
Immature DCs efficiently take up antigen but do not induce immunity, stellate cells with a lucent “empty”-appearing cytoplasm.
defined as the production of immune effectors and the establishment One method of categorizing DCs is to describe them based upon
of memory. For immune induction to occur, DCs require additional the tissue in which they reside. Lymphoid tissue–resident DCs have
stimuli that lead to an intricate differentiation process called “matura- undergone intensive study, especially in murine models. The scarcity of
tion.” Maturation involves changes in endocytic and antigen processing DCs in nonlymphoid tissues, on the other hand, limited understanding
machineries, production of chemokines and cytokines, and expression of their importance for many years and continues to render study of
of many cell-surface molecules, including those of the B7, TNF, and these cells challenging. Because circulating DCs are the most accessible
Notch ligand families. DCs have an endocytic system that is tightly subset in humans, they have received intense study; however, blood DCs
regulated and devoted to presentation of captured antigens, rather than may not reflect accurately the biology of tissue resident cells. Briefly, all
clearance and scavenging. DCs subsets are CD45+CD11c+class II+ cells that lack markers associ-
In the case of DCs derived from marrow and monocyte precursors, ated with T-cell, B-cell, erythroid, granulocytic, and NK lineages. How-
DC maturation is accompanied by exquisite changes in the endocytic ever, such a definition is not complete as some macrophages express this
system with attendant consequences for antigen processing and presen- phenotype yet are distinct from the DC lineage. Additional confidence
tation. During maturation, antigen uptake is dampened as a result of in a DC lineage is provided by expression of Flt-3 (FMS-like tyrosine
inactivation of a rho-guanosine triphosphatase termed cdc42. At the kinase 3, CD135), which mediates signals important in the differentia-
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same time, machinery associated with antigen processing is augmented. tion of this lineage, c-kit and/or CCR7.
Lysosomal processing is activated by assembly of an active proton An alternative method for classifying DC subsets separates the major
pump, which acidifies the lysosome so that processing of antigens and lineages as classical dendritic cells (cDCs) versus plasmacytoid dendritic
the MHC class II associated invariant chain can proceed. MHC–peptide cells (pDCs). cDCs are the most plentiful and incorporate lymphoid
complexes form within the endocytic system of the maturing DCs, 37,38 tissue–resident and nonlymphoid tissue–resident DCs. Although both
then traffic in distinct nonlysosomal compartments to the cell surface. pDCs and cDCs derive from a common progenitor, pDCs are distinct
Internalization and degradation of MHC II also occurs via ubiquitina- from cDCs in appearance (they resemble plasma cells) and they reside pri-
tion is also inhibited in mature DCs. DC maturation also increases marily in blood and lymphoid tissue, but are not found in nonlymphoid
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presentation on MHC I via, in part, the formation of an “immunopro- tissues. pDCs are important mediators of innate immunity, because of
teasome,” a combinatorial form of proteasome that increases the spec- their capacity to rapidly produce high levels of interferon (IFN)−α upon
trum of peptides destined to be presented on MHC I. 40 encounter with pathogens that engage the TLR-7 and TLR-9 receptors,
A hallmark of DC maturation in response to several stimuli is which are plentiful in this subset. cDCs are frequently further subdivided
upregulation of costimulatory molecules such as CD80 and CD86, into lymphoid-resident cDCs versus nonlymphoid-resident cDCs. In
resulting at least in part from production of inflammatory cytokines, mice, most lymphoid-resident cDCs are CD8α+CD11b− whereas most
particularly TNF-α. Importantly however, CD86 upregulation should nonlymphoid-resident cDCs are CD103+CD11b−. CD8α+CD11b−
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not be equated directly with immune activation, which requires other lymphoid tissue–resident cDC have a similar origin, phenotype, and
DC functions, such as those triggered by CD40 ligation, including pro- transcriptional profile as CD103+CD11b− nonlymphoid-resident
duction of cytokines such as IL-12 or type I interferons, and/or engage- cDC. In contrast, CD11b+ cDCs can be found in both lymphoid and
ment of other receptors such as CD70. 32 nonlymphoid tissue, and this subset is notable for its ability to derive
DCs enhance antibody formation by several mechanisms. The from monocytes in response to granulocyte-monocyte colony-stimu-
classical pathway involves induction of antigen-specific CD4+ helper lating factor (GM-CSF), monocyte colony-stimulating factor (M-CSF),
T cells, which then help B-cell growth and antibody secretion. How- and other inflammatory mediators. CD8α+ and CD8α− cDCs show
ever, DCs can also directly affect B cells to enhance immunoglobulin a remarkable division of labor in terms of the nature of induced host
(Ig) secretion and isotype switching, including production of the IgA response. While CD8α+ DCs efficiently cross-prime CD8+ T-cell
class of antibodies, which contribute to mucosal immunity. 41,42 DCs can immunity through MHC class I antigen presentation, CD8α− DCs
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induce a B-cell class switch in a CD40-independent manner, through stimulate predominantly CD4+ T-cell response through MHC class II
production of ligands such as B-lymphocyte stimulator (B-cell activat- presentation. These differences may be explained in part by the fact
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ing factor belonging to the TNF family [BAFF]) and a proliferation- that CD8α+ DCs have high endosomal pH, low antigen degradation,
induced ligand (APRIL), including T-cell–independent induction of high antigen export to cytosol, and more presynthesized stores of MHC
IgA antibodies to commensal organisms. Plasmacytoid DCs stimulate class I molecules. 47,48
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antibody responses to influenza virus in culture. Production of anti- In humans, essentially all DCs lack lineage markers for T
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bodies by any of these mechanisms may lead to interaction with DC cells, B cells, NK cells, and erythroid and granulocytic lineages,
FcγR and thereby an adaptive response by T cells. and express CD45 and MHC class II. Human pDCs are described as

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