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the functional defects allow the individual to
phoreplete periphery.
purge self-reactive T-cells by permitting new
According to this latest
emigrants to scan the periphery for tissuestudy, stimulated neonatal
RTEs secrete higher levels specific antigens without the danger of eliciting
autoimmunity? Neonates must uniquely cope
of effector cytokines
with lymphopenia and the absence of mature
(IL-2, IL-4 and IFN␥)
than do adult RTEs.1 Fur- peripheral T cells. Given that T cells undergoing homeostatic proliferation adopt a memory
thermore, RTEs from
cell phenotype and heightened function,7 the
neonates, but not from
adults, proliferate in reIL-7– driven proliferation of neonatal RTEs may
sponse to the key homeoboth help fill up empty space and provide a
T-cell development in the fetus and the neonate begins with immigration of
static cytokine IL-7 in the
population of memorylike T cells. Clearly, much
fetal liver–derived stem cells into the thymus. After intrathymic T-cell
absence
of
T
cell–receptor
remains to be learned about how the youngest
maturation is complete, RTEs exit the thymus and enter the lymphoid
periphery. RTEs are marked by green fluorescence in mice carrying a
stimulation. CD4⫹ RTEs
peripheral T cells cope with their adolescence
transgene-encoding green fluorescent protein driven by the RAG2 proand successfully transition into adulthood.
in
humans
also
show
inmoter. RTEs in the neonate enter a lymphopenic periphery and constitute
Acknowledgment: This work was supported
creased
IL-7–
driven
prothe majority of peripheral T cells. In the adult, stem cells arise from the bone
marrow, and after completing intrathymic maturation, the resulting RTEs
by National Institutes of Health grant R01
liferation, although no
exit the thymus and enter a lymphoreplete periphery, where they are
AI064318.
comparative analysis of
surrounded by a majority of mature T cells.
Conflict-of-interest disclosure: The author
neonatal and adult RTEs
declares no competing financial interests. ■
was presented in this
grafts, and analysis of T cell–receptor restudy.2 The heightened response of murine
arrangement excision circles. Each of these
neonatal RTEs to IL-7 is accompanied by
methods is problematic: they either result in
REFERENCES
differences in the kinetics of IL-7R␣ downcell death, thereby precluding functional ana1. von Boehmer H. Selection of the T cell repertoire:
regulation and downstream transcription facreceptor-controlled checkpoints in T cell development.
lyses, or involve surgical manipulation that can
tor activation. Analysis of radiation chimeras
Adv Immunol. 2004;84:201-238.
alter the very parameters being measured.
has indicated that the key differences between
2. Haines CJ, Giffon TD, Lu L-S, et al. Human CD4⫹ T
Recent advances have highlighted new
cell recent thymic emigrants are identified by protein tyneonatal and adult RTEs do not result solely
rosine kinase 7 and have reduced immune function. J Exp
means of identifying RTEs in both unmanipufrom their distinct stem cell source. Instead,
Med. 2009;206:275-285.
lated mice and humans, allowing the isolation
the availability of IL-7 and the density and
3. Boursalian TE, Golub J, Soper DN, et al. Continued
of live RTEs for functional and phenotypic
maturation of thymic emigrants in the periphery. Nat Imidentity of the cellular neighbors of RTEs may
⫹
munol. 2004;5:418-425.
analyses. In humans, CD4 RTEs are specificontribute to the distinct properties of adult
4. Hale JS, Boursalian TE, Turk GL, et al. Thymic output in
cally marked by expression of PTK7, a proand neonatal RTEs.
aged mice. Proc Natl Acad Sci U S A. 2006;103:8446-8452.
tein tyrosine kinase of unknown function in
Now that the “hows” are beginning to be
5. Makaroff LE, Hendricks DW, Niec RE, et al. Postthy2
T cells. In the mouse, RTEs can be identified
mic maturation influences the CD8 T cell response to antiunderstood, attention is likely to turn to the
as fluorescent peripheral T cells in mice exgen. Proc Natl Acad Sci U S A. 2009;106:4799-4804.
“whys” of continued postthymic maturation of
6. Opiela SJ, Koru-Sengul T, Adkins B. Murine neonatal
pressing a transgene encoding green fluoresT cells and the functional and phenotypic differ- recent thymic emigrants are phenotypically and functioncent protein under the control of the RAG2
ally distinct from adult recent thymic emigrants. Blood.
ences between neonatal and adult RTEs. Does
promoter.3 We have learned from these stud2009;113:5635-5643.
the 2- to 3-week transition period of postthymic
ies that thymic output (as a function of the size
7. Tanchot C, Le Campion A, Leaument S, et al. Naïve CD4⫹
T-cell maturation provide a means for further
lymphocytes convert to anergic or memory-like cells in T cell
of the generative compartment) is relatively conselecting the T-cell population for “best fit”? Do
deprived recipients. Eur J Immunol. 2001;31:2256-2265.
⫹
stant throughout life, that many more CD4
RTEs emigrate than can ultimately be incorpo● ● ● VASCULAR BIOLOGY
rated into the peripheral T-cell pool, and that in
both mice3-5 and humans,2 RTEs are phenotypiComment on Sörensen et al, page 5680
cally immature and functionally defective, compared with their mature counterparts.
Opiela et al have now contributed to this
---------------------------------------------------------------------------------------------------------------body of work by comparing the function and
phenotype of RTEs in the neonatal and adult
Manfred Gessler WUERZBURG UNIVERSITY
mouse.6 Such a comparison is clearly warThe VEGF-Dll4-Notch1 signaling cascade has taken center stage in angiogenesis,
ranted, given the known differences in neonabut it now appears that Dll1 ligands have precedence in arteries and even seem to
tal and adult T-cell biology. In the neonate,
control VEGF signaling.
RTEs differentiate from fetal liver stem cells
venous fate onto embryonic precursors prior
rteries and veins are structurally and
to enter a lymphopenic peripheral environfunctionally different types of vessels,
to formation of patent vessels and onset of
ment in which they constitute the majority of
and they display independent molecular signa- blood circulation. This has been shown most
peripheral T cells while in healthy adults,
tures. A genetic program imposes arterial or
elegantly in zebrafish and seems to hold true
RTEs comprise a minority of T cells in a lym-
Dll1 and Dll4: similar, but not the same
A
blood 2 8 M A Y 2 0 0 9 I V O L U M E 1 1 3 , N U M B E R 2 2
5375
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dence that other components may be equally important. Limbourg et al
showed that Dll1, a related
Notch ligand, is essential
for postnatal angiogenesis
with heterozygous Dll1⫹/⫺
mice exhibiting strongly
impaired reperfusion after
experimental hindlimb
ischemia.3 A complete Dll1
knockout is lethal with
bleeding around day 11
(E11) of embryonic development, but this seems to
be due to defects in surVascular Dll-Notch signaling. In fetal arteries (left), only Dll1 and not Dll4
appear to signal through Notch1 receptors to block the venous program
rounding tissues and not
and to mediate arterial gene expression in endothelia and in the surroundrelated to intrinsic vascular
ing smooth muscle layer in a VEGF-independent manner. This contrasts
functions. The availability
with sprouting angiogenesis in the capillary bed (right), where Dll4 is the
essential ligand that mediates the arterial program in stalk cells. VEGF
of hypomorphic and condiinduces this pathway and thereby reduces VEGF sensitivity in stalk cells.
tional knockout alleles of
Professional illustration by A. Y. Chen.
Dll14 now allow Sörensen
and colleagues to pinpoint a novel embryonic
for mammals as well.1 However, there is enorvascular defect that predicts a revised hierarmous plasticity in this system, allowing comchy of signaling.5
plete cell fate changes in response to external
stimuli during early embryogenesis. This
While Dll4 mutations (as well as mutaproperty is progressively lost with developtions of Notch receptors or Hey1/2 bHLH
mental age.2
effectors) show lethality after day 9.5 of embryonic development,1 Dll1 hypomorphs or
Blood vessels in the embryo are first
formed by vasculogenesis, the coalescence of
mice with endothelial-specific Dll1 deletion
precursors to form vascular tubes and meshsurvive until birth. Nevertheless, careful
works followed by remodeling and sprouting.
analysis of their blood vessels demonstrated
The current paradigm of sprouting angiogenthat arterial identity is progressively lost
esis holds that vascular endothelial growth
from larger vessels starting at day 13.5, the
factor (VEGF) signaling through VEGF retime point when endothelial Dll1 expression
ceptor 2 (Vegfr2), present on migrating tip
should begin. Surprisingly, Dll4 is still excells of newly forming sprouts, induces Dll4
pressed in these vessels, suggesting the exisligands. Dll4 in turn activates Notch signaling
tence of a switch making Dll4 incapable to
in following stalk cells, making them refracsustain Notch activity and expression of
tory to further VEGF-induced sprouting, in
arterial markers like Efnb2, Nrp1, or Hey1
part by reducing Vegfr2 and its coreceptor
and permitting expression of the vein
Nrp1. Dll4 also induces expression of arterial
marker Coup-TFII.
markers like Hey1/2 bHLH transcription
Interestingly, the reduction of Nrp1 exfactors and Efnb2 ligands, and it promotes
pression and thus the impaired capacity of
maturation and lumen formation. This is parendothelia to respond to VEGF in these mice
alleled by repression of vein endothelial markis not due to up-regulation of the venous reguers such as Nrp2, EphB4, and Coup-TFII,
lator Coup-TFII, which gets expressed only
with the latter being involved in reciprocal
later. Sörensen et al instead provide strong
antagonism with the Notch pathway compoevidence that in arteries Nrp1 and perhaps
nents Hey1 and Hey2 to determine arterial
VEGFR2 are directly induced by activated
versus venous cell fate.
Notch receptors, which are absent from Dll1
Although this model of sprouting angionegative or hypomorphic endothelia. Thus,
genesis and arterialization has gained broad
VEGF cannot be placed upstream of the Dll/
experimental support, there is increasing eviNotch cascade but rather it appears that Notch
5376
signaling enables VEGF responsiveness of
these cells.
What is striking is the differential severity of endothelial defects in Dll1 versus Dll4
KO mice. While a lack of Dll4 leads to very
early defects in angiogenesis and arterialization, this is much less so with Dll1. Although arterial markers are lacking and venous markers are up-regulated, this is still
compatible with embryonic development.
The perinatal lethality of the conditional
endothelial Dll1 knockouts may be due to
vascular problems, but this awaits further
study. Nevertheless, it seems that arterialization defects may be tolerated in later development or adults for some time, at least as
long as the animals are not subject to additional stress. This is reminiscent of the
rather limited arterialization of grafted veins
in human coronary arteries.6
The present study clearly shows that
there are parallel and noncompensating DllNotch signals in endothelial cells. Dll4 may
be more important early on in the capillary
bed, while Dll1 preferentially acts in arteries. Yet, the molecular basis for the differential function of these very similar ligands
acting on the same Notch1 receptor remains
unresolved. The principle of a VEGF-DllNotch signaling cascade in endothelia may
have to be revised for arteries with Dll1Notch1 acting not as a target, but as a facilitator of VEGF sensitivity.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Roca C, Adams RH. Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 2007;21:2511-2524.
2. le Noble F, Moyon D, Pardanaud L, et al. Flow regulates arterial-venous differentiation in the chick embryo
yolk sac. Development. 2004;131:361-375.
3. Limbourg A, Ploom M, Elligsen D, et al. Notch ligand
Delta-like 1 is essential for postnatal arteriogenesis. Circ
Res. 2007;100:363-371.
4. Schuster-Gossler K, Cordes R, Gossler A. Premature
myogenic differentiation and depletion of progenitor cells
cause severe muscle hypotrophy in Delta1 mutants. Proc
Natl Acad Sci U S A. 2007;104:537-542.
5. Sörensen I, Adams RH, Gossler A. DLL1-mediated
Notch activation regulates endothelial identity in mouse
fetal arteries. Blood. 2009;13:5680-5688.
6. Kudo FA, Muto A, Maloney SP, et al. Venous identity
is lost but arterial identity is not gained during vein graft
adaptation. Arterioscler Thromb Vasc Biol. 2007;27:
1562-1571.
28 MAY 2009 I VOLUME 113, NUMBER 22
blood
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2009 113: 5375-5376
doi:10.1182/blood-2009-02-205468
Dll1 and Dll4: similar, but not the same
Manfred Gessler
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