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C H A P T E R 23

DENDRITIC CELL BIOLOGY

Olivier Manches, Luciana R. Muniz, and Nina Bhardwaj

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Dendritic cells (DCs) are a sparsely distributed population of bone subsets, DC1 (CD141 ) and DC2 (CD1c ) and the plasmacytoid
marrow (BM)–derived mononuclear cells that exist in an “immature” DCs (pDCs). Prior studies suggesting that DCs can arise from other
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form in virtually all tissues in the body. DCs serve as professional multilineage sources may not be inconsistent, because these are
antigen-presenting cells (APCs) with an extraordinary capacity to generally speaking heterogeneous populations. In addition, hCDP
stimulate naive T lymphocytes (as well as B, natural killer [NK], can also give rise to pre-cDC progenitors in human cord blood, BM,
and NK T cells) and initiate primary immune responses. In their blood, and peripheral lymphoid organs. These pre-cDCs sustain the
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immature state, DCs detect and capture “danger signals” originat- CD1c and CD141 DC subsets, indicating that pDCs and cDCs
ing from microorganisms or their macromolecular constituents in arise during hematopoiesis from progenitors with already distinct
their resident tissues. Upon encountering such danger signals, DCs and restricted lineage potential. 16-18,18a Moreover, these pre-cDC
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undergo a complex series of events leading to their “maturation.” precursors in the blood can either be uncommitted or display early
Maturation of DCs is characterized by migration of DCs to draining commitment towards DC1 and DC2 development (pre-DC1 and
lymph nodes and by processing and presentation of antigens in the pre-DC2 phenotypes). Furthermore, Flt3-L given systemically to
context of antigen-presenting molecules such as major histocompat- humans has been shown to increase the pre-cDC pool. 17,19 Altogether,
ibility complex (MHC) and CD1 to naive T, B, and NK cells. these studies confirmed that there is a sequential pathway of DC
This chapter provides a snapshot of the current understanding of development that involves progenitors which display increasing
DC function as well as the potential clinical applications of DCs restricted commitment to give rise to the 3 major DC subsets.
as immunotherapeutic agents in diseases such as cancer, HIV, and The 3 DC subsets not only can be distinguished phenotypi-
autoimmunity. 2 cally, but also through molecular signatures. DC1 DCs, as briefly
described above, are phenotypically described by their expression of
CD141, XCR1 and CADM1; DC2s express CD1c and SIRPα; and
DENDRITIC CELL SUBSETS AND DEVELOPMENT pDCs express CD123. On the molecular level, DC1s express IRF8,
Batf3, Zbtb46 and Flt3; DC2s express ETS2, ID2, ZBTB46 IRF4
Extensive research has demonstrated that DCs exist in many and Flt3, while pDCs, as expected, express IRF7, TCF4, Spi-B and
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“flavors.” However, understanding of DC differentiation and the IL-3RA. In addition to the committed DC subsets, pre-cDCs are
different DC subsets is complicated by the heterogeneity of data also known to express specific markers such as CD45RA, CD123
obtained from in vitro human and mouse studies as well as in vivo (at low/intermediate levels), CD135, CD116, CD117 and CX3CR1
animal studies and limited in vivo human studies. In this chapter, and these can be used in the sorting of these precursors for DC1 and
we will concentrate on human DCs with little reference to murine DC2 development. 19
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models. Readers are encouraged to seek additional information in Under different culture systems, the CD34 HSCs have been
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several comprehensive reviews. 5–14 shown to give rise to CD34 CLA and CD34 CLA populations (skin
Most studies on the developmental origin of human DC subsets homing receptor cutaneous lymphocyte-associated antigen [CLA]),
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have used in vitro culture systems. The CD34 hematopoietic which differentiate to phenotypically distinguishable CD11c CD1a
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progenitor cells (HPCs) and blood monocytes are commonly used and CD11c CD1a imDCs, respectively. The former migrate into
as precursor cells for generating DCs in culture in vitro for both the skin epidermis and differentiate into Langerhans cells, and the
research and immunotherapeutic purposes. Monocytes, obtained latter localize to the skin dermis and other tissues and become inter-
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by simple adherence of HPCs to plastic, when exposed to a stitial imDCs. The human Langerhans cell DC subset has distinct
combination of granulocyte-macrophage colony-stimulating factor markers, including the presence of Birbeck granules, the expression
(GM-CSF) and interleukin-4 (IL-4), yield immature DCs (imDCs) of CD1a, and langerin, a member of the C-type lectin family of
that are comparable to some degree with tissue interstitial DCs. receptors involved in the uptake of pathogens. 22
Maturation of these different DCs can be induced by the addition In contrast to the blood “myeloid DCs” derived from pre-cDCs,
of various stimuli. Recently it was shown that monocyte-derived the “plasmacytoid DCs” contain “lymphoid” mRNA transcripts for
DCs (moDCs) constitute a subset of DCs that are not equivalent pre–T-cell α-chains, germline IgK, and Spi-B and are also called inter-
to blood DCs but resemble more inflammatory DC subsets 15 feron (IFN) type I-producing cells. These latter cells display a distinct
(Fig. 23.1). Pre-DCs and imDCs, similar to other cell types in the plasma cell morphology, contain abundant endoplasmic reticulum
immune system, are continuously produced at a steady rate and in (ER), and express high levels of IL-3αR but lack myeloid antigens,
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a pathogen-independent manner from CD34 hematopoietic stem including CD11c and most lineage markers. pDCs are found in the
cells (HSCs) within the BM. Fms-like tyrosine kinase-3 ligand peripheral blood, thymus, and many lymphoid tissues. The produc-
(Flt3L) and granulocyte colony-stimulating factor (G-CSF) represent tion of extraordinarily high levels of IFN type I by pDCs is unique to
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the key DC growth and differentiation factors. The development this cell type, and it may be important for initiating a strong antiviral
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of stromal cell culture systems comprising HSCs cultured with BM innate response and may promote maturation of bystander CD11c
mouse stromal cells and stem cell factor, GM-CSF, and Flt3L have cDCs to protect them from the cytopathic effect of viruses. 22–25 It is
led to the identification of a definitive pre-DC that gives rise to hypothesized that human cDCs and pDCs have evolved to recognize
DC subsets found in the blood. 15a,16,17 and respond to different pathogens in unique ways owing to their
Recent studies have shown that DCs originate from human granu- complementary expression of receptors for pathogen-associated
locyte monocyte dendritic cell precursors, which sequentially develop molecular patterns (PAMPs) (see Antigen Acquisition section),
into monocyte dendritic cell precursors, which subsequently give rise capacity to secrete either IFN type I or IL-12, antigen presentation,
to a common dendritic cell progenitor (hCDP) that is restricted and migration into secondary lymphoid organs. As mentioned, pDCs
to produce the three major subsets of DCs: 2 classical DC (cDCs) secrete high amounts of IFN-α upon viral infection but no IL-12
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