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HEMATOPOIESIS
Plasmacytoid dendritic cells: origin matters
Plasmacytoid dendritic cells (pDCs) are type I interferon–producing cells with antigen-presenting potential.
pDC populations are composed of transcriptionally and functionally heterogeneous cellular subsets with distinct
hematopoietic precursor origin.
Markus G. Manz
D
endritic cells (DCs) were
characterized about 45 years ago by
the late Nobel laureate Ralf Steinman
and colleagues. Since then, multiple
distinct subsets of the DC family have been
identified, all equipped with the hallmarks
of extracellular antigen uptake, migration,
antigen-presenting ability and induction
of activation or tolerance of the adaptive
immune system1. Plasmacytoid DCs
(pDCs), initially also called ‘plasmacytoid
T cells’ or ‘plasmacytoid monocytes’, are a
sub-population of DCs with large capacity
for producing type I interferon (and are thus
also called ‘natural interferon-producing
cells’)2. In this issue of Nature Immunology,
Fernandes et al. identify proliferating
immediate progenitors of pDCs in the
bone marrow of mice3. Moreover, they
developmentally and transcriptionally
delineate the heterogeneity of tissue pDC
populations and relate this heterogeneity
to differentiation pathways derived from
common DC progenitors (CDPs) and
cytokine receptor IL-7Rα​–expressing
pre-pDC progenitors that are newly
identified here.
On the basis of the discovery that
after in vitro stimulation with selected
cytokines, monocytes can differentiate
into either macrophages or DCs (including
Langerhans cell–like cells), it was
assumed that this would reflect the main
differentiation pathways in vivo. Subsequent
in vivo research has revealed that these
differentiation pathways are possible but
instead reflect inflammation- and repairdriven cellular differentiation. Somewhat
surprisingly, homeostasis-relevant tissue
macrophages and cells, such as microglia
and Langerhans cells, are embryonically
seeded, are long-lived, undergo self-renewal
and are replaced by adult hematopoietic
stem cell (HSC)-derived cells only after
tissue damage4. In contrast, lymphoid-tissue
classical DC (cDC) and pDC populations
do not undergo self-renewal and live only
few days (cDCs) or 1–2 weeks (pDCs)5.
Thus, both cDCs and pDCs require
continuous progenitor cell–derived input
to maintain the size of the population
in vivo at steady state.
During the past two decades, DC
subpopulations and their respective
differentiation pathways have been
defined in hematopoietic reconstitution
settings at steady state and, less frequently,
in situations of inflammation and
infection. This has been achieved through
the use of population-based and clonal
in vitro and in vivo transfer assays, as
well as genetic gain- and loss-of-function
approaches5–7. It is clear that Flt3L is
the key non-redundant cytokine for
the sustained quantitative development
of both cDCs and pDCs. The main cDC
populations at steady state in vivo are
derived from myeloid-restricted early
hematopoietic progenitors (MPs). MPs
generate CDPs8,9 via differentiation though
macrophage-DC progenitors10 or generate
CDPs directly11. CDPs subsequently
differentiate into pre-cDCs12 that then
produce cDCs.
While on a clonal level CDPs are able
to produce both cDCs and pDCs, their
overall pDC production is low relative
to the quantitative occurrence of pDCs
versus cDCs in vivo. Thus, alternative
pDC developmental pathways are
possible. Indeed, major pDC- and minor
cDC-differentiation potential has been
identified in a population tightly related
to and possibly in part derived from
CDPs (and myelo-lymphiod progenitors)
but lacking the surface marker M-CSFR
while expressing large amounts of the
transcription factor E2-2 (TCF4), which
is essential for pDC development13.
Fernandes et al. now revise this further3.
They first show in elegant classical in vitro
differentiation and in vivo transfer assays
that major pDC-differentiation potential
lies in Lin–c-Kitint–loFlt3+M-CSFR–IL-7Rα​+
cells, suggestive of lymphoid progenitor
derivation due to the expression of
IL-7Rα​. They further subdivide this
population into three subpopulations
on the basis of the expression of Ly6D,
a marker for early B cell differentiation,
and of SiglecH, a member of the sialic
acid–binding immunoglobulin-like lectin
family, which is expressed on pDCs.
Ly6D+SiglecH+ cell populations contain
purely pDC-committed cells with low
proliferation potential, which the authors
call ‘pre-pDCs’ in analogy to previously
defined pre-cDCs12. While CDPs and the
IL-7Rα​+ precursors exist at about the same
frequency in steady-state bone marrow,
they seem not to give rise to each other.
The in vitro and in vivo pDC output
from the newly identified IL-7Rα​+
population is five- to tenfold higher than
that from CDPs or M-CSFR–IL-7Ra– pDC
progenitors13. By transcriptional analysis,
Fernandes et al. then demonstrate pDClineage specification at the Ly6D+SiglecH+
progenitor stage3. Moreover, by bulk and
single-cell RNA-based next-generation
sequencing, focused protein-expression
analysis and computational modeling,
they reveal pDC heterogeneity in the bone
marrow and spleen: a smaller ‘pDC-like’
population that produces the cytokine
IFN-α​only after stimulation with the
oligodeoxynucleotide CpG-A, not after
stimulation with CpG-B, has higher
expression of major histocompatibility
complex class II after stimulation with
CpG-A, and has more-efficient antigen
processing and greater T cell–stimulating
ability (which resembles the characteristics
of cDCs); and a larger population of
‘regular’ pDCs, with a greater capacity to
produce IFN-α​and less T cell–stimulating
ability. On the basis of their transcriptional
profiles and function, ‘pDC-like’ cells
are derived from CDPs, while pDCs are
derived from IL-7Rα​+Ly6D+SiglecH+
progenitor cells, which suggests that the
different tissue pDC clusters might be
‘developmentally encoded’ (Fig. 1).
Such findings are important, as they
enhance understanding of the development
and heterogeneity of pDCs. Also, they
emphasize some limitations of research
approaches currently used, and they
stipulate new biological questions. In the
definition of hematopoietic stem and
Nature Immunology | www.nature.com/natureimmunology
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
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HSCs
MPPs
Microglia
MLPs
Granulocytes
NK, B, T cells
CLPs
MPs
MDPs
Langerhans cells
Pre-pDCs
CDPs
Monocyte
subtypes
Pre-cDCs
Macrophages
Inflammatory
macrophages
Inflammatory
DCs
c-Kitint–lo Flt3+
M-CSFR– IL-7Ra+
SiglecH+ Ly6D+
~0.1% of BM cells
c-Kitint
Flt3+
M-CSFR+
IL-7Ra–
~0.1% of
BM cells
pDC-like cells
cDC
subtypes
IRF8 independent
~5–30% of steady-state
spleen pDCs
Type 1 IFN+
APC function
pDCs
IRF8 dependent
~70–90% of steady-state
spleen pDCs
Type 1 IFN+++
Low APC function
Clonally or population-based documented major differentiation pathways
Differentiation pathways induced by inflammation or tissue damage
Immunophenotypic and functional populations or clonally defined cell populations
BM
BM and/or tissues
Embryonic origin and/or self-renewal
New findings in Fernades et al.
Fig. 1 | Differentiation pathways of antigen-presenting cells (DCs, pDCs and macrophages) in mice. Self-renewing HSCs generate highly proliferative, nonself-renewing progenitor populations that subsequently commit to lineage-restricted progenitor cells and final immature and mature effector populations.
These differentiation pathways are highly controlled environmentally and in a cell-intrinsic way. Arrows indicate experimentally documented differentiation
pathways (for multipotent progenitors (MPPs), myelo-lymphoid progenitors (MLPs), MPs, macrophage-DC progenitors (MDPs), CDPs, cDCs, common
lymphoid progenitors (CLPs) and pDCs). Newly identified pDC sub-populations and their progenitor and differentiation pathways identified by Fernandes
et al.3 are highlighted in the outlined oval: the main pDC populations in bone marrow (BM) and spleen are derived from an IL-Rα​+ progenitor cell (pre-pDC)
population that parallels the previously identified pre-cDC population, while a minor transcriptionally and functionally distinct pDC population, called
‘pDC-like cells’ by authors3, is independently derived from CDPs. pDCs and pDC-like cells are phenotypically similar but transcriptionally and functionally
distinct cell populations. NK, natural killer; IRF8, transcription factor; IFN, interferon. Credit: Marina Corral Spence/Springer Nature
progenitor cell (HSPC) sub-populations,
the in vivo long-term clonal ‘readout’
of HSCs allows relatively clear-cut
conclusions to be drawn. However, with a
decrease in the proliferative burst size of
HSPC populations in subsequent lineage
differentiation, robust readouts become
more challenging. A positive readout
defines a potential but does not necessarily
prove a major relevant pathway in steadystate or demand situations in vivo (as, for
example, those induced by γ​-irradiation
in this study), while a negative readout
might simply define insufficient assay
capacity. In addition, phenotype-based
selection of populations by flow cytometry
might lead, in some cases, to unavoidably
‘fuzzy’ population definitions. Remarkably,
many of the closely related populations
discussed here might include some overlap
due to varying signal strength, slightly
different gating in flow cytometry and, most
importantly, a continuum of expression
of the respective surface markers, such as
M-CSFR and IL-7Rα​, used to define cell
populations. Similarly, gene expression–
guided lineage tracing is challenged by
‘leakiness’ and/or insufficient reporting
tools. Finally, this might indeed be ‘fuzzy’
biology, as lineage commitment in vivo
might not be as linear as applied assays and
subsequent arrows on charts would suggest
(Fig. 1). These are issues that have kept the
field busy in the context of the definition of
many HSPC populations. The integration of
classical biological readouts with single-cell
RNA and computational analysis, as done in
the current study3, is pushing experimental
approaches and understanding to the
next level.
Additional studies are needed to
determine the environmental cues that
guide the development of pDCs and
pDC-like cells and that, in various tissues,
imprint their function in infectious
disease, autoimmunity, tissue repair
and also neoplastic disease. Furthermore,
while some hints of this already exist,
the existence, differentiation and function
of human homologs of pDCs will need
to be investigated.
❐
Markus G. Manz
Department of Hematology and Oncology, University
and University Hospital Zurich, Zurich, Switzerland.
e-mail: [email protected]
Published: xx xx xxxx
https://doi.org/10.1038/s41590-018-0143-x
Nature Immunology | www.nature.com/natureimmunology
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
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References
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2. Colonna, M., Trinchieri, G. & Liu, Y. J. Nat. Immunol. 5,
1219–1226 (2004).
3. Fernandes, P.R. et al. Nat. Immunol. https://doi.org/10.1038/
s41590-018-0136-9 (2018).
4. Ginhoux, F. & Jung, S. Nat. Rev. Immunol. 14, 392–404 (2014).
5. Geissmann, F. et al. Science 327, 656–661 (2010).
6. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. Annu. Rev.
Immunol. 31, 563–604 (2013).
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8. Naik, S. H. et al. Nat. Immunol. 8, 1217–1226 (2007).
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10. Fogg, D. K. et al. Science 311, 83–87 (2006).
11. Sathe, P. et al. Immunity 41, 104–115 (2014).
12. Liu, K. et al. Science 324, 392–397 (2009).
13. Onai, N. et al. Immunity 38, 943–957 (2013).
Competing interests
The author declares no competing interests.
Nature Immunology | www.nature.com/natureimmunology
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
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