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*
Institut National de la Santé et de la Recherche Médicale, Unite 429, Hôpital Necker-Enfants Malades, Paris, France; and
National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, which activates
macrophages, and by their ability to lyse virally infected cells and
tumor cells without prior sensitization. Although these characteristics
of NK cells are well documented, little is known about the genetic
program that orchestrates NK development or about the signaling
pathways that trigger NK effector functions. By crossing NK-deficient
common -chain (c) and recombinase activating gene
(RAG)-2 mutant mice, we have generated a novel alymphoid
(B-, T-, and NK-) mouse strain
(RAG2/c) suitable for NK complementation in vivo. The
role of the c-abl proto-oncogene in murine NK cell
differentiation has been addressed in hemopoietic chimeras generated
using RAG2/c mice reconstituted with
c-abl-/- fetal liver cells. The
phenotypically mature NK cells that developed in the absence of
c-abl were capable of lysing tumor targets, recognizing
"missing self," and performing Ab-dependent cellular cytotoxicity.
Taken together, these results exclude any essential role for
c-abl in murine NK cell differentiation in vivo. The
RAG2/c model thereby provides a novel approach to
establish a genetic map of NK cell development. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recombinase activating gene (RAG)3-2 blastocyst complementation system introduced by Alt and colleagues has proved instrumental in defining the potential role in T and B cell development of genes that give rise to embryonic lethality 15, 16 . Therefore, this approach can discriminate cell-intrinsic defects from in trans effects for any given mutation. Nevertheless, this system cannot be used to study gene effects on NK development, because RAG2-deficient mice develop NK cells 17 , thereby precluding the possibility of studying the donor-derived NK cells in the absence of competing mature host-derived cells. While other mouse models of NK cell deficiency are available, they are not satisfactory because they either rely on temporary Ab depletion of pre-existing NK cells 18 or they are associated with major defects in lymphopoiesis, lymphoid homeostasis, or autoimmunity 19, 20, 21 .
We have developed a novel alymphoid mouse strain that combines the
NK-deficiency found in common -chain (c; a shared
component of the receptors for IL-2, -4, -7, -9, and -15) mutant mice
with the T and B cell block due to mutation in the RAG2 gene
(RAG2/c double mutant mice). RAG2/c mice
offer certain advantages over RAG2 mice for studies involving lymphoid
reconstitution and are well suited for the in vivo study of NK cell
differentiation. In this report, we demonstrate the feasibility and
utility of the RAG2/c mouse model by examining the role
of the c-abl proto-oncogene in NK cell development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice with a null mutation in the c 20 were from
the fourth generation backcross to the C57BL/6 background. RAG2 mice
17 from the tenth generation backcross to C57BL/6 were kindly
provided by B. Rocha (Institut National de la Santé et de la
Recherche Médicale, Unite 345, Paris, France). C57BL/6 and
ß2-microglobulin-deficient C57BL/6 mice were obtained
from Centre de Développement des Techniques
Avancées/Centre National de la Recherche Scientifique
(Orleans, France). Mice doubly deficient in RAG2 and c
(RAG2/c) were obtained by intercrossing, and genotypes
were determined by PCR on DNA derived from tail snips (primer sequences
available from the authors). RAG2/c mice older than 6 wk
of age were used as recipients for lymphoid reconstitution. Mice
heterozygous for the c-abl mutation
(c-abl+/-; 9 , which had been backcrossed
>10 generations onto C57BL/6, were crossed with
c-abl+/- mice backcrossed for 5 generations
onto 129/Sv to generate day 18 c-abl-/- and
control (c-abl+/+ or
c-abl+/-) embryos. The morning of the vaginal
plug discovery was designated as day 0. The c-abl genotypes
of the embryos were determined by Southern blotting as described 9 .
Generation of hemopoietic chimeras
Pregnant female mice were sacrificed and the embryos were
explanted under sterile conditions. Fetal liver (FL) cell suspensions
were obtained by passage of the tissue through a 23-gauge needle.
RAG2/c mice were irradiated with 0.3 Gy from a cobalt
source and 4 h later were injected i.v. with 5 x
106 FL cells as a source of hemopoietic stem cells (HSC).
No differences were noted between reconstitutions made with
c-abl+/+ and c-abl+/-
FL-HSCs, which will be referred to as c-abl+.
Secondary transfers using bone marrow (BM) cells of
FL-HSC-reconstituted RAG2/c mice were performed by i.v.
injection of 107 total BM cells into irradiated (0.3 Gy)
RAG2/c recipients. All mice received tetracycline and
bactrim in the drinking water for the period following the transfer.
Flow cytometry
Single-cell suspensions were prepared from spleen, BM, thymus,
and liver. Erythrocytes were lysed in ammonium chloride, and cells were
resuspended in PBS with 3% FCS and 0.01% sodium azide. mAbs directly
conjugated to FITC, phycoerythrin, Tricolor (TRI), or biotin were used
for immunofluorescence analysis, including CD2, CD3, CD4, CD8,
TCR
ß, TCR
, CD11b, CD16 (FcRII/III), CD19, CD24, CD45R
(B220), IgM, CD90 (Thy-1), CD117 (c-kit), CD122 (IL2Rß),
CD132 (c), and the NK markers CD161 (NK1.1), DX5, Ly49A,
Ly49C/I, and Ly49G2 (PharMingen, San Diego, CA). Biotin
conjugates were revealed by streptavidin-TRI (Caltag, South San
Francisco, CA). Cells (105–106) were
first incubated with anti-CD16 and then stained with a mixture of
biotinylated and fluorochrome-labeled mAbs at saturating
concentrations, washed twice, and finally incubated with
streptavidin-TRI. Analysis was performed on a FACScan flow cytometer
using Lysis II software (Becton Dickinson, San Jose, CA). Dead
cells were excluded by their forward and side scatters parameters, and
an electronic gate was set to acquire (5–10 x 103)
lymphoid cells.
Generation of IL-15-activated NK cell cultures
Splenocytes were passed through nylon wool columns to remove B cells and macrophages. Nylon wool nonadherent (NWNA) cells were cultured in flat-bottom 24-well plates at 5 x 106 cells/ml in complete medium (RPMI 1640 with 10% FCS, 10-5 M ß-ME, 100 µg/ml streptamycin, and 100 U/ml penicillin), supplemented with 0.5 µg/ml of human IL-15 (R & D Systems, Minneapolis, MN). After 3–4 days, the nonadherent cells were removed, and the adherent lymphokine-activated killer (A-LAK) cells were refed and cultured until day 8–10. A-LAK cultures produced in this manner routinely contained >95% NK1.1+/CD3- cells.
In vitro cytotoxicity
A 51Cr release assay was used to measure NK activity in vitro as described 22 . Target cells (YAC-1, EL-4, or ConA-activated blasts) were labeled with 100 µCi 51Cr (ICN Pharmaceutical, Costa Mesa, CA), and 5 x 103 targets were incubated with graded numbers of effector cells in 200 µl of medium for 4 h. For Ab-dependent cellular cytotoxicity (ADCC), day 8–10 A-LAK cells were used as effectors, and targets were EL-4 cells coated with anti-CD90 (Thy-1.1) mAb. Radioactivity released into the cell-free supernatant was measured, and the percentage of specific lysis was calculated as following: 100 x (experimental release - spontaneous release/maximum release - spontaneous release). The spontaneous release never exceeded 15%.
In vivo NK cell-mediated tumor rejection
Recipient mice (H-2b) were injected s.c. (105 cells/0.1 ml) with class I-deficient RMA-S cells 23 . Mice were monitored for palpable tumors and were sacrificed when the tumor mass reached 15 mm in diameter. In this assay, NK-deficient mice succumb to tumors within 15 days, while C57BL/6 control mice as well as RAG2-/- mice do not develop tumors over the period of observation (>60 days).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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c mutant
mice
A novel alymphoid mouse strain was generated by intercrossing
RAG2-deficient 17 and c-deficient mice 20 .
RAG2/c mutant mice were viable and bred normally under
pathogen-free conditions. We characterized lymphoid development in
RAG2/c vs RAG2 or control C57BL/6 mice. In contrast to
RAG2 mice, RAG2/c mutants were almost completely
depleted in early lymphoid precursors (Table I
and Fig. 1A). For example,
CD19+ BM cells were almost completely absent in
RAG2/c mice, and thymic cellularity was further reduced
100-fold compared with RAG2 mice (10,000-fold fewer thymocytes than
controls). The effect of the c mutation on the
development of these early lymphoid precursors likely reflects their
requirement for IL-7/IL-7R/c signaling for survival
(reviewed in 24 . As expected, no mature IgM+ B cells
or ß+ T cells were found in mice harboring the RAG2
mutation (Fig. 1C). In addition, RAG2/c mice
completely lacked NK1.1+ cells in the BM (Fig. 1B) and spleen (data not shown). The presence of functional
NK cells lacking the NK1.1 marker in RAG2/c mice
appeared unlikely based on the following criteria: 1) splenocytes from
RAG2/c mice show no natural cytotoxicity against YAC-1
targets in vitro at E:T ratios of 300:1, 2) RAG2/c mice
fail to augment IFN- blood levels following administration of murine
IL-12 in vivo, and 3) RAG2/c mice fail to reject
allogeneic BM grafts or MHC class I-deficient tumors in vivo (data not
shown). In contrast, RAG2 mice retain these three NK cell effector
functions (Ref. 17 and data not shown). Taken together, these results
demonstrate that RAG2/c mice have no mature B, T, or NK
cells and are therefore a suitable host for in vivo NK complementation.
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c mice using
c-abl-/- HSC
We hypothesized that a defect in NK cell function could contribute
to the increased susceptibility of c-abl-/-
mice to infections 9, 10 . Most c-abl-/- mice
succumb at 3 wk of age, which is coincident with the first appearance
of functional NK cells in the mouse 13, 14 . To investigate the role
of c-abl in NK development, we generated hemopoietic
chimeras in irradiated (0.3 Gy) RAG2/c mice using FL
cells from c-abl+ and
c-abl-/- embryos. Serial blood sampling
demonstrated lymphoid reconstitution beginning at 4 wk posttransfer,
which normalized by 8 wk posttransfer (data not shown). At this point,
chimeras were sacrificed, and lymphoid development was assessed in the
BM, thymus, spleen, and liver. In chimeras injected with
c-abl+ FL cells, full lymphoid reconstitution
was observed. Normal absolute numbers of thymic and splenic lymphocytes
were found, representing increases of 100- to 10,000-fold compared with
nonmanipulated RAG2/c mice (Table I
). The appearance of
mature T and B cells in the chimeras (Fig. 2) demonstrated that donor-derived
precursors could fully differentiate in this setting, and the donor
origin of the resultant NK cells was confirmed by staining with
anti-c mAb (Fig. 3C). Thus, all mature lymphoid
subsets (B, T, and NK) could be generated from wild-type FL cells
following injection into irradiated RAG2/c mice. These
results demonstrate that the lymphoid defects in RAG2/c
mice are cell-intrinsic and that expression of the c in
BM stromal or gut epithelial cells is not required for normal lymphoid
development.
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c chimeras was then assessed. The
absolute numbers of lymphoid cells in the BM, thymus, and spleens of
c-abl-/- chimeras were similar to that of
control chimeras (Table I). Moreover, no obvious differences in the
development of phenotypically defined lymphoid subsets could be
discerned between the two groups of chimeras. Similar percentages and
absolute numbers of NK1.1+CD3- NK cells,
CD4+ or CD8+ ß T cells, T cells,
NK1.1+ ß T cells, B220+IgM+ B
cells, and B220+IgM- pre-B cells were found in
the lymphoid organs of c-abl-/- and control
RAG2/c chimeras (Fig. 2, A and B,
Fig. 3, A and B, and data not shown). Moreover,
the absolute numbers of most lymphocytes subsets were also comparable
in chimeric animals to normal C57BL/6 mice, although the development of
thymic and peripheral NK1.1+ ß T cells were slightly
reduced in both c-abl-/- and control chimeras
(Fig. 3B). Phenotype and function of c-abl-/- NK cells
A more detailed analysis of the NK cells generated in
c-abl-/- RAG2/c chimeras was
performed. Using a panel of Abs detecting Ags expressed by NK cells, a
normal percentage and expression level of CD2, CD11b, CD16, CD45R, DX5,
CD122, CD90, and CD117 was found on c-abl-/-
NK1.1+CD19-TCRß- spleen
cells compared with control NK cells (data not shown). In particular,
the expression levels of the inhibitory receptors of the Ly49 family
(Ly49A, Ly49C/I, and Ly49G2) and the frequencies of these different
Ly49+ NK "subsets" in c-abl-/-
RAG2/c chimeras was normal (data not shown).
The lytic capacity of freshly isolated splenic
c-abl-/- NK cells was tested in vitro.
c-abl-deficient NWNA spleen cells demonstrated normal levels
of natural cytotoxicity against YAC-1 thymoma targets (Fig. 4A). Day 8–10 A-LAK cells
also mediated efficient lysis of YAC-1 targets, as well as Ab-mediated
cell cytotoxicity against Ab-coated EL-4 cells (Fig. 4, B
and C). Moreover, both c-abl+ and
c-abl-/- A-LAK cells could discriminate
between class I-negative and class I-positive ConA-activated blasts,
lysing the former but not the latter (Fig. 4D). Taken
together, these results suggest that c-abl function is not
required 1) for NK cell development and maturation, 2) for NK cell
recognition and inhibition by self-MHC, and 3) for NK cell receptor
calibration in vivo (reviewed in 25 .
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c chimeras were capable of in vitro expansion in
response to IL-15. In addition, the A-LAK cultures generated in this
fashion were IL-12 responsive (data not shown), ruling out any
essential role of c-abl in the mitogenic responses of NK
cells to IL-12 or IL-15.
To investigate in vivo NK cell function, we examined whether
c-abl RAG2/c chimeric animals could eliminate
MHC class I-negative tumor cells. Mice were injected s.c. with
Tap1-deficient (RMA-S) cells 26 , and tumor formation was
monitored. Both c-abl+ and
c-abl-/- RAG2/c chimeras were
able to control growth of MHC class I- tumor cells (data
not shown), demonstrating normal NK lytic activity in vivo.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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c mutations
(RAG2/c). Although a number of immunodeficient mouse
models exist (such as beige, nude,
scid, RAG, xid, and combinations thereof),
RAG2/c mice offer considerable advantages over these
strains including 1) a complete absence of mature T, B, and NK cells,
2) a stable immunophenotype, 3) no increased propensity to spontaneous
tumor formation, and 4) no autoimmune phenomena due to defective
lymphoid homeostasis. The alymphoid nature of RAG2/c
mice will permit the construction of mice with defined immune systems,
which should prove useful in further defining the role of different
lymphoid subsets (NK, NK-T, T, and ß T cells) during immune
responses to infectious pathogens. The immunodeficiency in
RAG2/c mice permits stable hemopoietic engraftment
(using either FL or adult BM HSCs) across classical histocompatibility
barriers and without irradiation (our unpublished observations).
We have recently found that RAG2/c mice accept human PBL
xenografts to a similar extent as nonobese diabetic/SCID mice
27 . Thus, RAG2/c mice should be useful for a
number of applications in lymphoid development, immune responses, tumor
immunology, and xenotransplantation.
Alt and colleagues revolutionized the analysis of genes involved in T
and B cell development by introducing the RAG2 blastocyst
complementation system 15 . This powerful technique has been used
extensively to study the function of "embryonic lethal" genes in
the immune system (reviewed in 16 . Despite this major advance,
RAG2 complementation cannot be used to study NK differentiation
(because RAG-deficient mice have NK cells; 17 or early lymphoid
precursors (as these develop normally in the absence of RAG genes). The
early precursors in RAG2 mice in principle could compete with the
mutant donor cells, thereby blocking their development and giving the
impression that a given gene is essential for T and/or B cell
development. Because RAG2/c mice are also severely
depleted in T and B lymphocyte precursors compared with their RAG2
counterparts (Fig. 1), they should offer less competition at these
early stages of lymphoid development. Consistent with this hypothesis,
we have recently found that c-kit deficient
(W/W) FL cells can give rise to normal numbers of T
lymphocytes when grafted in RAG2/c mutant mice (our
unpublished observations), whereas the same experiment performed
in RAG2-deficient mice failed to generate T lineage cells 28 .
In this report, we have used RAG2/c mice to assess the
role of the c-abl protein tyrosine kinase in NK development.
Our results rule out an essential role for c-abl in NK
differentiation in vivo. In the absence of c-abl, normal
numbers of NK cells can develop in a phenotypically normal fashion and
acquire a lytic capacity for a variety of targets in vitro and in vivo.
The proper expression of inhibitory Ly49 receptors suggests that
c-abl is not required for the calibration of the NK cell
repertoire (reviewed in 25 . Moreover, c-abl-deficient
A-LAKs demonstrated natural cytotoxicity and ADCC activities similar to
their c-abl+ counterparts, and
c-abl-/- NK cells could eliminate MHC class
I- tumor cells in vivo. Therefore,
c-abl-/- NK cells appear normal in their
development and in their effector functions.
The nature of the defect in c-abl mutant mice that causes
lymphopenia and that predisposes these mice to infection remains
elusive. Because c-abl expression is ubiquitous, effects of
c-abl deficiency in trans may be difficult to
dissociate from cell-intrinsic effects of the mutation. Previous
studies using one strain of c-abl mutant mice showed
variable defects in BM B cell development and peripheral lymphocyte
function 11 . These results suggested that the c-abl
mutation could affect the function of T and B cells, although
c-abl was not required for the development of these cells
9, 10, 11, 12 . Interestingly, the observed B and T cell defects could be
transferred to normal mice by adult BM, but not by FL 11 , strongly
suggesting an in trans effect. Our results confirm that T
and B cells are not strictly dependent on c-abl expression
within fetal hemopoietic cells. Transfer of BM HSCs from adult
c-abl-/- RAG2/c chimeras to
secondary RAG2/c recipients also generated normal B, T,
and NK cell development (our unpublished observations), arguing
against a cell-intrinsic difference in
c-abl-/- fetal vs adult HSCs. In addition,
pre-B (B220+IgM-) cells from
c-abl-/- RAG2/c chimeras could
generate mature B cells in vitro (our unpublished observations),
in contrast to previous reports using freshly isolated pre-B cells from
c-abl-/- mice 11 . A major defect in NK cell
functions as responsible for the susceptibility to infection observed
in c-abl mutant mice also appears unlikely.
RAG2/c chimeras generated with
c-abl-deficient FL cells show no increased mortality when
housed in conventional animal facilities up to 8 mo postgraft. Taken
together, these results argue against any important cell-intrinsic
defects of the c-abl mutation for T, B, and NK cell
development.
The complete absence of NK cells in RAG2/c mice extends
the RAG2 complementation system 16 to identify the genes responsible
for and implicated in NK differentiation. Through the generation of
somatic or hemopoietic chimeras in RAG2/c mice, it
should now be possible to establish the genetic map for the development
of the NK cell lineage in vivo.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. James P. Di Santo, Institut National de la Santé et de la Recherche Médicale, Unite 429, Pavillon Kirmisson, Hôpital Necker Enfants Malades, 149, rue de Sèvres, 75015 Paris, France. E-mail address:
3 Abbreviations used in this paper: RAG, recombinase activating gene; ADCC, Ab-dependent cellular cytotoxicity; A-LAK, adherent lymphokine-activated killer; BM, bone marrow; c, common cytokine receptor -chain; FL, fetal liver; HSC, hemopoietic stem cell; NWNA, nylon wool nonadherent.
Received for publication September 28, 1998. Accepted for publication December 3, 1998.
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References |
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gene. Proc. Natl. Acad. Sci. USA 91:9402. chain. Proc. Natl. Acad. Sci. USA 92:377. chain. Br. J. Hematol. 103:335.[Medline]
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U. Schleicher, A. Hesse, and C. Bogdan Minute numbers of contaminant CD8+ T cells or CD11b+CD11c+ NK cells are the source of IFN-{gamma} in IL-12/IL-18-stimulated mouse macrophage populations Blood, February 1, 2005; 105(3): 1319 - 1328. [Abstract] [Full Text] [PDF]
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M. Zamisch, B. Moore-Scott, D.-m. Su, P. J. Lucas, N. Manley, and E. R. Richie Ontogeny and Regulation of IL-7-Expressing Thymic Epithelial Cells J. Immunol., January 1, 2005; 174(1): 60 - 67. [Abstract] [Full Text] [PDF]
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B. R. Winders, R. H. Schwartz, and D. Bruniquel A Distinct Region of the Murine IFN-{gamma} Promoter Is Hypomethylated from Early T Cell Development through Mature Naive and Th1 Cell Differentiation, but Is Hypermethylated in Th2 Cells J. Immunol., December 15, 2004; 173(12): 7377 - 7384. [Abstract] [Full Text] [PDF]
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G. Schlecht, S. Garcia, N. Escriou, A. A. Freitas, C. Leclerc, and G. Dadaglio Murine plasmacytoid dendritic cells induce effector/memory CD8+ T-cell responses in vivo after viral stimulation Blood, September 15, 2004; 104(6): 1808 - 1815. [Abstract] [Full Text] [PDF]
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C. A. J. Vosshenrich, A. Cumano, W. Muller, J. P. Di Santo, and P. Vieira Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment PNAS, July 27, 2004; 101(30): 11070 - 11075. [Abstract] [Full Text] [PDF]
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 S. Vollstedt, S. Arnold, C. Schwerdel, M. Franchini, G. Alber, J. P. Di Santo, M. Ackermann, and M. Suter Interplay between Alpha/Beta and Gamma Interferons with B, T, and Natural Killer Cells in the Defense against Herpes Simplex Virus Type 1 J. Virol., April 15, 2004; 78(8): 3846 - 3850. [Abstract] [Full Text] [PDF]
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B. Goudeau, F. Huetz, S. Samson, J. P. Di Santo, A. Cumano, A. Beg, A. Israel, and S. Memet I{kappa}B{alpha}/I{kappa}B{epsilon} deficiency reveals that a critical NF-{kappa}B dosage is required for lymphocyte survival PNAS, December 23, 2003; 100(26): 15800 - 15805. [Abstract] [Full Text] [PDF]
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 S. Di Donna, K. Mamchaoui, R. N. Cooper, S. Seigneurin-Venin, J. Tremblay, G. S. Butler-Browne, and V. Mouly Telomerase Can Extend the Proliferative Capacity of Human Myoblasts, but Does Not Lead to Their Immortalization Mol. Cancer Res., July 1, 2003; 1(9): 643 - 653. [Abstract] [Full Text] [PDF]
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T. Ranson, C. A. J. Vosshenrich, E. Corcuff, O. Richard, W. Muller, and J. P. Di Santo IL-15 is an essential mediator of peripheral NK-cell homeostasis Blood, June 15, 2003; 101(12): 4887 - 4893. [Abstract] [Full Text] [PDF]
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F. Stevenaert, K. Van Beneden, A. De Creus, V. Debacker, J. Plum, and G. Leclercq Ly49E expression points toward overlapping, but distinct, natural killer (NK) cell differentiation kinetics and potential of fetal versus adult lymphoid progenitors J. Leukoc. Biol., June 1, 2003; 73(6): 731 - 738. [Abstract] [Full Text] [PDF]
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R. T. Strait, S. C. Morris, K. Smiley, J. F. Urban Jr., and F. D. Finkelman IL-4 Exacerbates Anaphylaxis J. Immunol., April 1, 2003; 170(7): 3835 - 3842. [Abstract] [Full Text] [PDF]
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T. Ranson, C. A. J. Vosshenrich, E. Corcuff, O. Richard, V. Laloux, A. Lehuen, and J. P. Di Santo IL-15 availability conditions homeostasis of peripheral natural killer T cells PNAS, March 4, 2003; 100(5): 2663 - 2668. [Abstract] [Full Text] [PDF]
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D. B. Klug, C. Carter, I. B. Gimenez-Conti, and E. R. Richie Cutting Edge: Thymocyte-Independent and Thymocyte-Dependent Phases of Epithelial Patterning in the Fetal Thymus J. Immunol., September 15, 2002; 169(6): 2842 - 2845. [Abstract] [Full Text] [PDF]
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T. C. C. Kerre, G. De Smet, M. De Smedt, A. Zippelius, M. J. Pittet, A. W. Langerak, J. De Bosscher, F. Offner, B. Vandekerckhove, and J. Plum Adapted NOD/SCID model supports development of phenotypically and functionally mature T cells from human umbilical cord blood CD34+ cells Blood, March 1, 2002; 99(5): 1620 - 1626. [Abstract] [Full Text] [PDF]
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I. Douagi, F. Colucci, J. P. Di Santo, and A. Cumano Identification of the earliest prethymic bipotent T/NK progenitor in murine fetal liver Blood, January 15, 2002; 99(2): 463 - 471. [Abstract] [Full Text] [PDF]
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F. Colucci, E. Rosmaraki, S. Bregenholt, S. I. Samson, V. Di Bartolo, M. Turner, L. Vanes, V. Tybulewicz, and J. P. Di Santo Functional Dichotomy in Natural Killer Cell Signaling: Vav1-Dependent and -Independent Mechanisms J. Exp. Med., June 18, 2001; 193(12): 1413 - 1424. [Abstract] [Full Text] [PDF]
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G. Moreau, M. Leite-de-Moraes, S. Ezine, J. P. Di Santo, M. Dy, and E. Schneider Natural killer cell-dependent apoptosis of peripheral murine hematopoietic progenitor cells in response to Fas cross-linking: involvement of tumor necrosis factor-{alpha} Blood, May 15, 2001; 97(10): 3069 - 3074. [Abstract] [Full Text] [PDF]
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F. Colucci, S. I. Samson, R. P. DeKoter, O. Lantz, H. Singh, and J. P. Di Santo Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells Blood, May 1, 2001; 97(9): 2625 - 2632. [Abstract] [Full Text] [PDF]
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M. Y. Braun, I. Grandjean, P. Feunou, L. Duban, R. Kiss, M. Goldman, and O. Lantz Acute Rejection in the Absence of Cognate Recognition of Allograft by T Cells J. Immunol., April 15, 2001; 166(8): 4879 - 4883. [Abstract] [Full Text] [PDF]
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P. Auguste, D. B. Gürsel, S. Lemière, D. Reimers, P. Cuevas, F. Carceller, J. P. Di Santo, and A. Bikfalvi Inhibition of Fibroblast Growth Factor/Fibroblast Growth Factor Receptor Activity in Glioma Cells Impedes Tumor Growth by Both Angiogenesis-dependent and -independent Mechanisms Cancer Res., February 1, 2001; 61(4): 1717 - 1726. [Abstract] [Full Text]
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S. Bregenholt, P. Berche, F. Brombacher, and J. P. Di Santo Conventional {{alpha}}{{beta}} T Cells Are Sufficient for Innate and Adaptive Immunity Against Enteric Listeria monocytogenes J. Immunol., February 1, 2001; 166(3): 1871 - 1876. [Abstract] [Full Text] [PDF]
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A. A. Ashkar, J. P. Di Santo, and B. A. Croy Interferon {gamma} Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy J. Exp. Med., July 17, 2000; 192(2): 259 - 270. [Abstract] [Full Text] [PDF]
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F. Colucci, D. Guy-Grand, A. Wilson, M. Turner, E. Schweighoffer, V. L. J. Tybulewicz, and J. P. Di Santo A New Look at Syk in {alpha}{beta} and {gamma}{delta} T Cell Development Using Chimeric Mice with a Low Competitive Hematopoietic Environment J. Immunol., May 15, 2000; 164(10): 5140 - 5145. [Abstract] [Full Text] [PDF]
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C. Soudais, T. Shiho, L. I. Sharara, D. Guy-Grand, T. Taniguchi, A. Fischer, and J. P. Di Santo Stable and functional lymphoid reconstitution of common cytokine receptor gamma chain deficient mice by retroviral-mediated gene transfer Blood, May 15, 2000; 95(10): 3071 - 3077. [Abstract] [Full Text] [PDF]
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F. Colucci and J. P. Di Santo The receptor tyrosine kinase c-kit provides a critical signal for survival, expansion, and maturation of mouse natural killer cells Blood, February 1, 2000; 95(3): 984 - 991. [Abstract] [Full Text] [PDF]
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 B. A. Croy, A. A. Ashkar, K. Minhas, and J. D. Greenwood Can Murine Uterine Natural Killer Cells Give Insights Into the Pathogenesis of Preeclampsia? Reproductive Sciences, January 1, 2000; 7(1): 12 - 20. [Abstract] [PDF]
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F. Colucci, M. Turner, E. Schweighoffer, D. Guy-Grand, V. Di Bartolo, M. Salcedo, V. L. J. Tybulewicz, and J. P. Di Santo Redundant Role of the Syk Protein Tyrosine Kinase in Mouse NK Cell Differentiation J. Immunol., August 15, 1999; 163(4): 1769 - 1774. [Abstract] [Full Text] [PDF]
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