Blackwell Science, LtdOxford, UKCMICellular Microbiology 1462-5822Blackwell Publishing Ltd, 200359573580Review ArticleDrosophila blood cellsM. Meister and M.

Lagueux

Cellular Microbiology (2003) 5(9), 573–580 doi:10.1046/j.1462-5822.2003.00302.x

Microreview

Drosophila blood cells

Marie Meister and Marie Lagueux* mechanisms. In this context, Drosophila has been the
UPR 9022 du CNRS, IBMC, 15 rue René Descartes, model of choice in the two last decades, to unravel the
67084 Strasbourg, France. molecular mechanisms of non-adaptive host defence.
Drosophila immunity includes two complementary facets
which are humoral and cellular immunity. Most of the
Summary
recent progress relates to Drosophila humoral immunity.
Drosophila blood cells or haemocytes belong to three Infection by bacteria or fungi triggers the rapid and mas-
lineages: plasmatocytes, crystal cells and lamello- sive production in the fat body, which is the liver counter-
cytes. There is no equivalent of a lymphoid lineage in part in insects, of a number of antimicrobial peptides and
insects which have no adaptive immunity. Haemato- other effectors. Two major signalling pathways control this
poiesis is under the control of a number of transcrip- process which are called the Toll and the Imd pathways
tion factors and signalling pathways (such as GATA (reviewed in Hoffmann and Reichhart, 2002). The intrac-
factors, JAK/STAT or Notch pathways) most of which ellular components of both pathways, as well as the extra-
have homologues which participate in the control of cellular cascades that lead to their activation, are currently
mammalian haematopoiesis. Drosophila plasmato- under intense investigation in various laboratories.
cytes are professional phagocytes reminiscent of the Opposed to this, cellular immunity, the second facet of
cells from the mammalian monocyte/macrophage lin- Drosophila host defence, has only recently attracted
eage. Several receptors responsible for recognition of renewed interest. We would like in this review to give an
microorganisms or apoptotic corpses have been update of our current knowledge on haematopoiesis in
identified, which include a Scavenger Receptor, a Drosophila, and on the functions of the various blood cell
CD36 homologue and a peptidoglycan recognition or haemocyte types.
protein. Crystal cells contain the enzymes necessary
for humoral melanization that accompanies a number
I. Haematopoiesis in Drosophila
of immune reactions. The production of melanin gen-
erates, as by-products, cytotoxic free radicals that are Two phases of haematopoiesis
believed to participate in the killing of pathogens.
Drosophila haematopoiesis occurs in two phases during
Finally, lamellocytes represent a cell type that specif-
development, and gives rise to three haemocyte lineages
ically differentiates after parasitism of Drosophila
that share characteristics with mammalian myeloid lin-
larvae and forms a capsule around the invader.
eages. Drosophila, like all arthropods, has no equivalent
Encapsulation together with melanization eventually
of a lymphoid lineage. A first haematopoietic wave takes
kill the parasite within the capsule.
place in the second half of embryogenesis when a popu-
lation of haemocytes originate in the procephalic meso-
Introduction derm and migrate to colonize the whole embryo along
invariant paths (Tepass et al., 1994). These cells, called
Innate immunity is phylogenetically the oldest defence
plasmatocytes, act as macrophages as they eliminate
system in the animal kingdom. It evolved before adaptive
apoptotic cells (Franc et al., 1996; 1999). A second pop-
immunity which has arisen only recently in evolution and
ulation differentiates simultaneously nearby the anterior
is the hallmark of vertebrate immunity. Like all inverte-
region of the gut where it remains localized around the
brates, insects defend themselves through innate immune
proventriculus (Lebestky et al., 2000). These cells are
crystal cells (see below) and their role in the embryo is
unknown. Towards the end of embryogenesis, the precur-
Received 31 March, 2003; revised 2 May, 2003; accepted 7 May,
2003. *For correspondence. E-mail M.Meister@ibmc.u-strasbg.fr; sors of the lymph glands form in the lateral mesoderm,
Tel. (+33) 03 88 41 70 32; Fax (+33) 03 88 60 69 22. and migrate dorsally to prefigure the first paired lobes of

© 2003 Blackwell Publishing Ltd

574 M. Meister and M. Lagueux
the organ (Rugendorff et al., 1994). The lymph glands are
the main site of haematopoiesis during larval stages
(Shrestha and Gateff, 1982; Rizki and Rizki, 1984; Lanot
et al., 2001). They are composed of a variable number of
paired lobes that are located along the dorsal vessel
(Fig. 1). In the posterior lobes they contain essentially
undifferentiated precursor cells called prohaemocytes.
More anteriorly they mostly contain fully differentiated
haemocytes which are released into the circulation. Cir-
culating haemocytes (Fig. 1) comprise a majority of plas-
matocytes which are the dedicated phagocytes, and a
small proportion (<5%) of crystal cells. Crystal cells con-
tain crystalline inclusions that correspond to enzymes
necessary for humoral melanization (see below). An addi-
tional cell type is found in the anteriormost lobes of the
lymph glands that displays features of intense protein
synthesis. These ‘secretory cells’ are never seen in circu-
lation: they probably correspond to a variation on the
plasmatocyte theme as intermediate forms are often
found in the lymph glands. Finally, a third independent
haemocyte lineage exists in larvae, but is seldom
observed in healthy animals. These cells called lamello-
cytes differentiate massively in the lymph glands after
parasitization and are large flat cells devoted to encapsu-
lation of invaders too large to be phagocytosed by plas-
matocytes (Fig. 1). A commonly encountered immune
threat for Diptera (flies) is parasitism by Hymenoptera
(wasps) species that lay their eggs in Diptera larvae (Car-
ton et al., 1986). The cellular reaction that fends off para-
sites thus involves the production of a specific, inducible
haemocyte lineage.
At the onset of metamorphosis, the lymph glands
release large numbers of active phagocytes that are
called pupal macrophages and play a crucial role in tissue
Fig. 1. Drosophila haemocytes.
A. Scanning electron microscopy of a larval
haematopoietic organ. The lymph glands are
organized as paired lobes along the dorsal ves-
sel (arrow). Anterior is to the left.
B. Circulating haemocytes stained with DAPI.
Plasmatocytes are small round cells whereas
lamellocytes (arrows) are larger and flattened.
C. Phase-contrast microscopy of circulating
crystal cells (arrows) with conspicuous crystal-
line inclusions.
D. Confocal image of phagocytosis of E. coli
(K12 Alexa Fluor 594) by GFP-labelled plasma-
tocytes from a tep1-GFP larva.
E–G. Encapsulation of parasitoid wasp eggs/
larvae. A wasp larva is surrounded by lamello-
cytes (blue nuclei in E); the cell layer becomes
thicker while melanization of the parasite is ini-
tiated (arrowhead in F); eventually the wasp
egg/larva is totally melanized within the lamel-
locyte capsule (G). Lamellocytes are visualized
with a lacZ enhancer trap marker in E and F.
H–J. Transmission electron microscopy of a
plasmatocyte (H), a crystal cell (I) and lamello-
cytes (J). Bars: 50 mm (A, E–G), 20 mm (B),
10 mm (C, D), 2 mm (H–J).
© 2003 Blackwell Publishing Ltd, Cellular Microbiology, 5, 573–580

remodelling as they phagocyte cells of doomed larval
structures. In this process they also eat up the remainder
of the lymph glands, and at later stages no haematopoi-
etic organ can be found (Lanot et al., 2001). This modifi-
cation of the properties of plasmatocytes and the
simultaneous dispersal of the lymph glands is under the
control of the steroid hormone ecdysone (Lanot et al.,
2001; Sorrentino et al., 2002) which orchestrates all tissu-
lar modifications related to metamorphosis. In Drosophila
adults, the only haemocyte type that is present is the
plasmatocyte, and the pool of adult haemocytes likely
derives from larval plasmatocytes. Given their morpholog-
ical and functional features, it is generally considered that
Drosophila plasmatocytes resemble the mammalian
monocyte/macrophage lineage.
Transcriptional control of haematopoiesis
Our understanding of regulation of haemocyte prolifera-
tion and specification comes from genetic analysis of
mutants (Fig. 2). Control of haemocyte proliferation was
investigated at the larval stage and it was recently shown
that the unique Drosophila homologue of PDGFR/
VEGFR, named PVR, together with one of its three puta-
tive ligands PVF2, plays a crucial role in the control of
prohaemocyte proliferation (Munier et al., 2002). This find-
ing was essentially demonstrated by the dramatic effect
of PVF2 overexpression in larvae, which resulted in a 300-
fold increase in blood cell counts, due to excessive prolif-
eration of prohaemocytes at the expense of differentiation.
A comparable (40-fold) effect was obtained by pan-hae-
matopoietic overexpression of an activated form of Ras,
and this effect is mediated by the Raf/MAPK pathway
(Asha et al., 2003). It is however, not documented yet
whether the proliferation signal produced by PVF2/PVR is
transmitted via the Ras/Rak/MAPK pathway. This prolifer-
ation effect of PVF2/PVR observed at larval stages does
not apply to the embryonic stage where PVF/PVR were
rather proposed to establish a guidance system respon-
sible for the migration of the plasmatocytes throughout the
embryo (Cho et al., 2002).
Early data have also implicated the JAK/STAT and the
Toll pathways in the control of circulating haemocyte num-
bers as gain-of-function mutations of JAK and of Toll result
in increased blood cell counts (Luo et al., 1995; Lemaitre
et al., 1995), whereas loss-of-function mutations in the Toll
pathway have the opposite effect (Qiu et al., 1998).
Haemocyte identity in embryos is specified by the GATA
factor Serpent (Srp; Rehorn et al., 1996; Waltzer et al.,
2002). A similar function for srp is likely to occur at larval
stages as its expression is recorded before all differentia-
tion markers in prohaemocytes (Lebestky et al., 2000). It
is proposed that srp might be required both for the spec-
ification of haemocyte primordium within the mesoderm
© 2003 Blackwell Publishing Ltd, Cellular Microbiology, 5, 573–580
Drosophila blood cells 575
at an early embryonic stage, and later for gene expression
during their maturation. Several transcription factors and
signalling pathways have been demonstrated to govern
lineage specification in Drosophila haematopoiesis. Two
Zinc-finger transactivators, Gcm (Glial Cells Missing, Ber-
nardoni et al., 1997; Lebestky et al., 2000) and Gcm2
(Alfonso and Jones, 2002) are required for plasmatocyte
fate in the embryo, and this has also been documented
for Gcm at the larval stage. The crystal cell fate is
instructed in larvae by the Serrate/Notch pathway (Duvic
et al., 2002; Lebestky et al., 2003) and the Runx1-related
Lozenge transcrition factor (Lebestky et al., 2000). The
Friend-of-GATA homologue U-shaped antagonises crystal
cell development (Fossett et al., 2001). Transcription fac-
tors that determine lamellocyte development are not yet
identified. Mutations in three genes have long been known
to stimulate lamellocyte production: these are Toll and
JAK dominant gain-of-function, and cactus loss-of-
function mutations (Lemaitre et al., 1995; Luo et al., 1995;
Qiu et al., 1998). It is however, possible that the effect of
these mutations on haemocyte differentiation is indirect.
It is striking that most of the players in Drosophila hae-
matopoiesis identified so far are counterparts of gene
products that are also central to mammalian haemato-
poiesis, such as GATA factors, the Notch pathway, Runx1
or the JAK/STAT pathway to cite but a few examples. It
appears that the same building blocks are used with dif-
ferent combinations to control haematopoiesis in inverte-
brates and vertebrates.
II. Haemocyte functions
Drosophila that are deprived of haemocytes are clearly
sensitized to infection. This was shown in larvae carrying
a mutation called domino which results in extremely
reduced haemocyte counts. When this mutation is com-
bined with mutations affecting humoral immunity (imd) or
melanization, resistance of larvae to infection is strongly
decreased compared to single mutants (Braun et al.,
1998). Similarly, inactivation of adult haemocytes by mas-
sive injection of polystyrene beads reduced the ability of
imd flies to fight bacterial infection (Elrod-Erickson et al.,
2000). Haemocytes are responsible for a number of
immune functions in Drosophila, among which phagocy-
tosis, encapsulation and melanization have been docu-
mented. We have outlined the current data on these
immune reactions below.
Phagocytosis
In vertebrates, the elimination of microorganisms and the
removal of apoptotic cells are achieved by the same
phagocytes. However, whereas phagocytosis of non-self
particles induces inflammation, that of apoptotic cells
576 M. Meister and M. Lagueux
either downregulates or suppresses inflammation (Vandi-
vier et al., 2002). Phagocytosis occurs in several steps.
The first consists in the attachment of the phagocyte to
the targeted particle followed by alteration of the cytosk-
eleton and internalization. The engulfed target is then
destroyed within phagosomes by lysosomal enzymes,
reactive oxygen species and nitric oxide (Jones et al.,
1999). The latter phases are likely conserved between
invertebrates and vertebrates, involving namely actin-
remodelling and vesicule trafficking (Rämet et al., 2002a).
It has been proposed that phagocytosis of both apop-
totic cells and microorganisms requires two processes:
tethering, followed by actin-dependent engulfment
(reviews in Aderem and Underhill, 1999; Fadok and
Chimini, 2001; Hoffmann et al., 2001; Greenberg and
Grinstein, 2002). Tethering of the target to the phagocyte
is achieved by receptors that will either directly recognize
determinants on microorganisms or apoptotic cells, or
bind through opsonizing molecules. Most of these recep-
tors have a broad recognition spectrum for both endoge-
nous and exogenous molecules, and may participate in
the phagocytosis of both types of targets. Mammalian
examples are the Scavenger Receptor family (qualified as
‘molecular fly papers’ by Krieger et al., 1993). Tethering
favours a tight association between the target and the
phagocyte, and clustering of the binding proteins then
mediates phagocytosis. The release of the signal trigger-
ing the appropriate on/off switch of inflammation seems
to be dependent on the engulfment receptor that is simul-
taneously recruited. A few receptors are able to initiate
engulfment, and they also participate in the recognition of
the target. For ingestion of microorganisms, well studied
receptors are the Mannose Receptor, that binds sugar
moieties on microorganisms, two proteins of the integrin
family, CR3 (aMb2) and CR4 (aXb2) that are receptors
for the opsonizing complement factor C3bi, and the Fcg
receptors that recognize antibodies. Phagocytosis of apo-
ptotic cells is dependent on the recognition of phosphati-
dylserine by its receptor (PS-R), but can also be mediated
by two integrins aVb3 and aVb5, the tyrosine kinase MER
and CD91 (Henson et al., 2001; Huynh et al., 2002).
In Drosophila, plasmatocytes are responsible for the
disposal of both microorganisms (Fig. 1) and apoptotic
cells. The mechanisms by which they recognize and
engulf their targets are poorly understood. Phagocytosis
of apoptotic cells at the embryonic stage requires wild-
type function of the croquemort gene, which encodes a
CD36 homologue (Franc et al., 1996, 1999). In mammals
CD36 is a class B Scavenger Receptor which acts in
concert with the vitronectin receptor (aVb3) and PS-R to
engulf apoptotic corpses (Fadok et al., 1998). A homo-
logue of PS-R has also been described in Drosophila but
no functional studies have yet demonstrated a role for this
receptor in apoptotic cell removal (Henson et al., 2001).
A scavenger receptor, dSR-CI with similar broad ligand
recognition as mammalian class A Scavenger Receptor
was identified by Pearson et al. (1995). dSR-CI can medi-
ate binding to both Gram-negative and Gram-positive bac-
teria when transfected into CHO cells and participates to
some extent to the binding of these microorganisms to S2
cells, a primary Drosophila blood cell culture (Rämet
et al., 2001). PGRP-LC, a Peptidoglycan Recognition Pro-
tein, mediates phagocytosis of Gram-negative, but not
Gram-positive bacteria by S2 cells (Rämet et al., 2002a).
Interestingly, PGRP-LC belongs to a family of 12 members
in Drosophila (Werner et al., 2000). This putative mem-
brane bound protein is involved in the induction of the fat
body Imd transduction pathway, leading to the production
of antibacterial peptides after an infection with Gram-neg-
ative bacteria (Gottar et al., 2002). Similarly, PGRP-SA
which is a soluble PGRP, is required for the proper induc-
tion of the Toll pathway after infection with Gram-positive
bacteria (Michel et al., 2001). Gottar et al. (2002) have
suggested that PGRPs are sensors which define the type
of microbial infection and drive the proper signalling path-
way. An additional family of recognition proteins found in
insects are the Gram-negative bacteria-binding proteins
or GNBPs which all contain gluconase-like domains.
Three cDNAs encoding GNBPs have been cloned from a
Drosophila blood cell line library. Although their role in
phagocytosis has not been demonstrated, it was shown
that one GNBP (DGNBP-1) can bind LPS and b-1,3-
glucan (Kim et al., 2000). Although there is good evidence
that Croquemort, dSC-RI or PGRP-LC can mediate
phagocytosis of target particles, there is no demonstration
that they can by themselves trigger internalization without
assistance from co-receptors.
The Drosophila genome harbours six genes encoding
thiolester-containing proteins or TEPs (Lagueux et al.,
2000). These proteins are related to the a2macroglobulin/
complement factor C3 family as they share the 12 signa-
ture domains characteristic of these proteins, which com-
prise the well conserved thiolester motif region. However,
TEPs clearly form a new group in this family due to a
distinct cystein arrangement in their C-terminal region. All
putative TEPs possess a signal peptide indicating that
they are secreted proteins. The transcription of three out
of six tep genes (tep1, 2 and 4) is upregulated after an
immune challenge and tep1 and tep4 are mainly
expressed in haemocytes (Lagueux et al., 2000; and M.
Lagueux, unpubl. obs.). We have proposed that TEPs
function during an immune response either as opsonins
to promote phagocytosis, in a C3-like manner, or as pro-
tease inhibitors, in an a2-macroglobulin manner. The best
evidence so far, in favour of the opsonin hypothesis,
comes from studies in an other insect, Anopheles gam-
biae. Levashina et al. (2001) found similar TEP proteins
in this model insect and could show that phagocytosis of
© 2003 Blackwell Publishing Ltd, Cellular Microbiology, 5, 573–580

Gram-negative bacteria in an Anopheles blood cell line is
strongly reduced when transcription of the atep1 gene is
impaired.
It is likely that plasmatocytes also send signals to other
immunocompetent tissues. When larvae are infected per
os with the phytopathogenic Erwinia carotovora, they
respond by the activation in the fat body of the Imd path-
way with subsequent production of antibacterial peptides
(Basset et al., 2000). In mutant larvae with a reduced
number of haemocytes, such as domino larvae for
instance, the Imd pathway is not activated in response to
infection. This indicates that haemocytes act as messen-
gers that somehow convey information to the fat body in
the case of bacterial infection. However, the nature of the
signal is still unknown.
Encapsulation
Some 50 hymenopteran species are reported parasites of
Drosophila (Carton et al., 1986). The wasp females lay
their eggs in the haemocoel of young larvae. This foreign
body is detected by plasmatocytes which are the first line
immune supervisors in circulation. They readily attach to
the chorion of the egg (Russo et al., 1996) and a few
hours later a strong cellular reaction is observed in the
haematopoietic organ with enhanced proliferation,
increase in crystal cell numbers (Sorrentino et al., 2002),
and massive differentiation of lamellocytes (Lanot et al.,
2001). Lamellocytes then form a multilayered capsule
around the invader, which is ultimately accompanied by
blackening due to melanization (Fig. 1). Within the cap-
sule, the parasite is eventually killed, by asphyxiation or
by the local production of cytotoxic free radicals, quinones
or semiquinones (Nappi et al., 1995; 2000). The whole
process of parasite encapsulation raises several intriguing
questions. The first relates to the signal that is produced
by plasmatocytes once they have recognized an invader
which they cannot phagocyte. This signal is perceived by
prohaemocytes in the lymph glands which then differenti-
© 2003 Blackwell Publishing Ltd, Cellular Microbiology, 5, 573–580
Drosophila blood cells 577
ate into an adapted haemocyte lineage. The identity of the
signal has yet to be determined. Thus lamellocytes, to
some extent, exhibit adaptive characteristics as they only
differentiate in response to a specific immune challenge.
They form several layers of cells around the parasite, to
which they are attracted either by the previously attached
plasmatocytes, or by wasp determinants. The nature of
this mechanism is also unknown.
Melanization
Humoral melanization in arthropods produces black pig-
ment as a result of the activation of a biochemical pathway
that converts tyrosine to melanin (reviews in Ashida and
Brey, 1997; Söderhäll and Cerenius, 1998). Melanization
is controlled by a cascade of serine proteases that ulti-
mately cleave the zymogen prophenoloxidase to its active
form. Phenoloxidase then catalyses the oxidation of phe-
nols to quinones, which polymerize non-enzymatically to
form melanin. It was shown in lepidopterans that the cas-
cade is activated by initial recognition of non-self molec-
ular patterns such as b-1,3-glucans, peptidoglycan or
LPS. The different elements of the cascade are not yet
elucidated in Drosophila, but a key control serpin has
been recently identified that restricts phenoloxidase activ-
ity to the site of injury or infection (De Gregorio et al.,
2002; Ligoxygakis et al., 2002). Serpin-27 A regulates the
melanization cascade through the specific inhibition of
prophenoloxidase processing by the terminal serine pro-
tease. Three genes encoding prophenoloxidases [Fujim-
oto et al., 1995; Berkeley Drosophila Genome Project
(BDGP)] are present in the Drosophila genome, and in
larvae they are specifically expressed in crystal cells (M.
Meister, unpubl. obs.), which, once activated, readily dis-
rupt and deliver their content into the haemolymph where
the enzymes can function. A number of intermediate com-
pounds formed during melanin synthesis are cytotoxic
(see above, killing of the parasite), it is thus important to
strictly control the localization of the reaction. This is
Fig. 2. Regulation of Drosophila haematopoie-
sis. Blood cell identity is conferred by the GATA
factor Serpent (srp). Proliferation is controlled
by the PVF2/PVR, the Ras/Raf, the Toll and the
JAK/STAT pathways. Crystal cell specification
is under the control of the Notch (N) pathway
and the Runx1 homologue Lozenge (lz) trans-
activator, and antagonized by the Friend-of-
GATA homologue U-shaped (ush). Plasmato-
cytes are specified by two Glial-cells-missing
(gcm) transactivators, then further differentiate
into pupal macrophages under the impulse of
the steroid hormone ecdysone (Ecd). Lamello-
cyte specification requires wild-type functions
of Notch and of the JAK/STAT pathway.
578 M. Meister and M. Lagueux
achieved not only by the regulatory serpins, but also by
the fact that activated phenoloxidase shows a tendency
to aggregate (Ashida and Brey, 1997).
Melanization was proposed to participate in the sealing
of a wound before the more elaborate epithelial wound
healing process (Lai-Fook, 1966) that takes several days.
This is based namely on the observation that Drosophila
melanization-deficient mutants show defects in wound
healing with excessive bleeding and reduced survival
(Rämet et al., 2002b). These observations could indicate
a role for melanization in the coagulation process, or that
the proteolytic cascades leading to melanization and to
coagulation share components. Nothing is known to date
on molecular mechanisms responsible for coagulation in
Drosophila. It will thus be challenging to determine how
melanization and coagulation are activated in this model,
and how closely they are related.
Extracellular matrix production
Drosophila haemocytes are known to produce abundant
extracellular matrix material. Indeed many proteins have
been purified from the supernatant of Kc cell cultures
which are of haematopoietic origin (review in Fessler
et al., 1994; Nelsson et al., 1994; Goto et al., 2001).
Among these, laminins, collagen IV, tenascinm, glutactin,
peroxidasin and haemolectin were subsequently found
to be strongly expressed in embryonic and larval
haemocytes. However, the almost complete absence of
haemocytes in domino larvae does not result in apparent
structural tissue defects and so the significance of this
synthesis is not yet clear. Some of these molecules exhibit
peculiar features, namely peroxidasin which contains a
putative peroxidase domain associated with several leu-
cine-rich repeats similar to those found in the extracellular
domain of Toll family members (Nelsson et al., 1994).
Haemolectin displays similarity with the von Willebrand
factor which in vertebrates plays a role in haemostasis
(Goto et al., 2001). However, as no mutants for both these
genes are available, their function has not been assessed
to date.
Conclusion
The field of Drosophila immunity has witnessed significant
development over the last few years, thereby fuelling our
general understanding of innate immunity. Opposed to
this, for a long time Drosophila has failed to be a leading
model in the analysis of haematopoiesis and of blood cell
functions. A number of recent studies have now demon-
strated that it has a role to play in the understanding of
proliferation, commitment and differentiation of haemato-
poietic precursors, thanks to its powerful genetics and to
the increasing numbers of blood cell markers. It also
should help to gain insight, in the future, into molecular
mechanisms of functions that are the hallmarks of mye-
loid-type blood cells.
Acknowledgements
The authors thank Jules Hoffmann for continued support. Work
in their laboratory is supported by CNRS, NIH grant 1PO1
AI44220-02 to A. Ezekowitz and J. Hoffmann, the French Min-
istère de l’Education Nationale, de la Recherche et de la Tech-
nologie, EntoMed, Exelixis and l’Association de la Recherche
contre le Cancer.
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