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310 Part IV: Molecular and Cellular Hematology Chapter 21: Dendritic Cells and Adaptive Immunity 311

Lin−classII+CD303(BDCA2)+CD304(BDCA4)+, whereas human cDC studies provided important fundamental insights into DC biology, such
blood subsets generally correlate with lymphoid tissue cDC subsets. as the link between DC maturation and their immunogenicity, 63,64 they
Human cDCs are either CD1c(BDCA1)+ or CD141(BDCA3)+, with did not exploit the biology of naturally occurring DCs and their sub-
the CD1c+ subset being significantly more plentiful than the CD141+ sets. These studies also emphasized the need to combine vaccine-based
subset. In humans, BDCA3+ DCs have been proposed as human equiv- approaches with strategies to overcome suppressive elements in the
alents of murine CD8α+ DCs, and may have superior cross-presentation tumor bed, including inhibitory immune checkpoints, and address the
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capability compared to other human DC subsets. However, the capac- vaccine-induced induction of regulatory T cells. Recent promising
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ity for cross-presentation is not restricted to this subset of human DCs. clinical results with T-cell immune checkpoint blockade such as with
The DEC205/CD205 lectin receptor is also a useful marker for DCs in antibodies against PD1/PDL1 in human cancer is setting the stage for
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human lymph nodes. Nonlymphoid tissue–resident DCs in humans the next generation of combination therapies with vaccines. 66,67 In addi-
remain incompletely characterized, with the exception of Langerhans tion to T cells, DCs are also being explored to activate other immune
cells. First described more than 100 years ago, Langerhans cells are cDCs cells such as innate NKT cells. Combination of NKT-cell–targeted vac-
found in the epidermis, characterized by a “tennis racket” appearance by cine with low-dose lenalidomide led to synergistic immune activation
light microscopy as a result of internalized Langerin, which localizes in and tumor regressions in early myeloma. 68
“Birbeck granules.” Langerhans cells are characterized by expression of Another strategy involves targeting antigens directly to DCs in situ.
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CD1a as well as EpCAM and CD207(Langerin). Uncontrolled prolifera- Coupling antigens to antibodies against DEC205, an antigen-uptake
tion of Langerhans cells is responsible for the clinical disorder known as receptor on DCs, leads to enhanced activation of T-cell immunity in
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Langerhans cell histiocytosis (LCH). several models. Even in this setting, DC activation is essential to elicit
Further insights into the functional diversity of DC subsets has immunity and targeting antigens to DEC205 in steady state results in
come from discovery of distinct transcriptional factors that underlie the induction of tolerance. Early clinical studies with targeting anti-
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their development and functional properties. For example, z-DC, gens to DEC205 combined with approaches to activate DCs demon-
was identified as a transcriptional factor regulating the development strate clear induction of humoral and cellular immune responses.
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of classical DCs. 53,54 Functional specialization of DC subsets is likely to Promising but preliminary results in patients who receive T-cell check-
impact the next generation of vaccines, as discussed in “Dendritic Cells point blockade following the vaccine supports the investigation of com-
in Immunotherapy” below. bination approaches. Other emerging approaches to targeting DCs in
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One of the most important discoveries in DC biology has been situ include nanoparticles. These technologies hold promise for flexi-
identification of a clonogenic DC progenitor within the marrow that is bility and personalization of the vaccine, but the nature of optimal DC
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committed to the DC lineage and unable to give rise to other cell types. subset or adjuvant/DC maturation stimulus remains to be clarified.
Such progenitors, described as pro-DCs can generate plasmacytoid and It is notable that potent human vaccines, such as the yellow fever vac-
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CD8α+ and CD8α− classical DCs, but no other cell subset. 55,56 Subse- cine, simultaneously engage multiple DC subsets, raising the prospect
quent work confirmed that the committed DC progenitor derives from that to optimize the generation of T-cell immunity a combination of DC
a more primitive cell that is capable of giving rise to monocytes and subsets will need to targeted in vivo. 73
macrophages. Progenitors can also be identified that specifically gave A setting where the biology of DCs plays a central role in hema-
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rise to cDCs but not pDCs. In mice, administration of Flt-3 ligand tology is allogeneic stem cell transplantation. The immunologic activ-
expands progeny of DC-committed progenitors. This series of discov- ity of donor T cells in allogeneic stem cell transplantation is a critical
eries dispelled the notion that DCs in vivo were largely derived from factor for eradicating residual malignancy, a process termed GVL, but
inflammation driven monocyte differentiation and firmly established can also lead to detrimental GVHD. There is considerable evidence that
DCs as a distinct hematopoietic lineage. Still, in states of inflammation, the induction of GVHD is dependent on the remaining host antigen-
DCs can be induced from mature monocytes in the presence of inflam- presenting cells of which DCs are the most potent. 74,75 The role of DCs
matory mediators such as GM-CSF and M-CSF. in mediating the GVL effect is less-well understood, although a role for
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DCs has been implicated. DC subsets, particularly pDCs, have also
emerged as critical regulators of autoimmune hematologic disorders
DENDRITIC CELLS IN such as immune thrombocytopenia in children. 77
Consequently, targeting DCs may be of benefit in the setting of
IMMUNOTHERAPY autoimmunity as well as GVHD.
In view of their central role as antigen-presenting cells, DCs have been
targeted to both boost T-cell immunity in the setting of resistance REFERENCES
against pathogens/tumors or suppress T cells in the setting of autoim-
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mune disease. Although both are relevant to hematologic diseases, 1. Steinman RM, Banchereau J: Taking dendritic cells into medicine. Nature 449:419–426,
much of the current effort has been in the context of vaccination to 2007.
boost T-cell immunity against tumors. Immunity to standard subcuta- 2. Belkaid Y, Oldenhove G: Tuning microenvironments: Induction of regulatory T cells by
dendritic cells. Immunity 29:362–371, 2008.
neously injected protein vaccines is also likely impacted by the biology 3. Melief CJ: Cancer immunotherapy by dendritic cells. Immunity 29:372–383, 2008.
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of lymph node–resident and migratory DC subsets. Two broad strat- 4. Beutler BA: TLRs and innate immunity. Blood 113:1399–1407, 2009.
egies have been attempted to harness the ability of DCs to boost T-cell 5. Rakoff-Nahoum S, Medzhitov R: Toll-like receptors and cancer. Nat Rev Cancer 9:
57–63, 2009.
immunity. One approach involves adoptive transfer of antigen-loaded 6. Zitvogel L: Dendritic and natural killer cells cooperate in the control/switch of innate
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DCs. In most of these studies, DCs were generated ex vivo from pre- immunity. J Exp Med 195:F9-F14, 2002.
cursors such as blood monocytes, although some of these studies also 7. Ruggeri L, Capanni M, Urbani E, et al: Effectiveness of donor natural killer cell allore-
activity in mismatched hematopoietic transplants. Science 295:2097–2100, 2002.
utilized more primitive progenitors, such as CD34+ hematopoietic stem 8. Walzer T, Dalod M, Robbins SH, et al: Natural-killer cells and dendritic cells: “l’union
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cells or circulating DCs. One of the first studies involved the injec- fait la force”. Blood 106:2252–2258, 2005.
tion of idiotype-pulsed DCs against lymphoma. Most of these studies 9. Munz C, Steinman RM, Fujii S: Dendritic cell maturation by innate lymphocytes: Coor-
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dinated stimulation of innate and adaptive immunity. J Exp Med 202:203–207, 2005.
were small, and while DCs were well tolerated, they led to only modest 10. Fujii S, Shimizu K, Hemmi H, Steinman RM: Innate Valpha14(+) natural killer T cells mature
clinical effects in terms of objective tumor regression. Although these dendritic cells, leading to strong adaptive immunity. Immunol Rev 220:183–198, 2007.

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