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*
Allergy Research Laboratory, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, and
Department of Obstetrics and Gynecology, University of Montreal, Quebec, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production at the
single-cell level. F(ab')2 fragments of CD47 mAb or the
synthetic peptide 4N1K, corresponding to the CD47 binding site of
thrombospondin, display the same activity. CD47 engagement does not
change the phenotype of IL-12-primed cells from Th1 to Th2 or affect
IL-4-induced Th2 cell development. Moreover, CD47 mAb inhibits IL-12-
but not IL-4-induced IL-2 production as well as IFN- in primary
cultures, which was correlated with a decrease of the IL-12Rß2 chain
expression. Inclusion of exogenous IL-2 at priming corrects IL-12R
expression as well as the inhibition of Th1 cell development. The data
thus underline the role of IL-2 in Th1 cell development and further
suggest that targeting IL-2 and IL-12 simultaneously may have some
therapeutic advantage in Th1 autoimmune
diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
lymphotoxin-
(LT-),3 and TNF-
but no or little IL-4 and IL-5; Th2 cells produce high levels of IL-4,
IL-5, IL-9, IL-10, and IL-13 but no or little IFN- and LT-. These
subsets of T cells have distinct regulatory and effector functions, and
the inappropriate selection of Th1 or Th2 phenotype results in
ineffective or disease-promoting immune responses (2). As
recently reviewed (3, 4, 5), several factors are implicated
in the regulation of naive T cell differentiation into Th1 or Th2
effectors. These include 1) the intensity and the nature of
TCR-mediated activation signal, 2) the strength and the nature of
costimulatory signals, 3) the cytokine and hormonal milieu in which T
cells are primed, and 4) the genetic background of the naive T cells.
Among all of these factors, cytokines appear to exert the most
important role, with IL-4 and IL-12 promoting Th2 and Th1 responses,
respectively. The other factors may act by influencing the production
of these two cytokines at priming.
IL-12 promotes Th1 cell development by signaling maturing T cells
through a high affinity receptor consisting of two chains, IL-12Rß1
and IL-12Rß2, that are differentially regulated (review in Ref.
6). IL-12Rß1 is constitutively expressed on several
types of cells, including resting T and B cells, which are not
responsive to IL-12 (7). The coexpression of these two
chains is required for IL-12 responsiveness and Th1 cell
development. Expression of IL-12Rß2 on naive T cell activation is
enhanced by Th1-inducing factors (IFN-, IFN-, and IL-12 itself)
and down-regulated by Th2-promoting factors (IL-4,
PGE2, and glucocorticosteroids) (8, 9). Thus, IL-12 responsiveness increases during Th1 cell
differentiation, whereas it disappears during Th2 cell development
(10, 11, 12). The latter phenomenon is associated with, but
perhaps not entirely dependent on, IL-12Rß2 down-regulation. Indeed,
forced expression of IL-12Rß2 during Th cell differentiation does not
prevent the development of Th2 cells or confer IL-12 responsiveness
(13, 14).
CD47 Ag, also known as integrin-associated protein, is a widely
expressed multispan transmembrane protein, which is physically and
functionally associated with
vß3 integrin, the
vitronectin receptor (15, 16). Indeed,
CD47- cell lines expressing
vß3 do not bind
vitronectin-coated beads, and CD47-deficient mice rapidly die of
Escherichia coli peritonitis, a phenomenon directly
associated with a reduction in leukocyte activation in response to
ß3, but not ß2,
integrin ligation (17). CD47 has also been implicated in
leukocyte transendothelial migration (18, 19). Its natural
ligand, thrombospondin (TSP), is a homotrimeric extracellular matrix
protein that is produced not only by platelets but also by monocytes
and alveolar macrophages. TSP is transiently expressed at high
concentration in damaged and inflamed tissue (20). A
potential role for TSP and CD47 in immune regulation was recently
suggested by the finding that they regulate the in vitro production of
IL-12 (21, 22). Engagement of CD47 by mAb, TSP, or 4N1K (a
peptide of the C-terminal domain of TSP selectively binding CD47)
inhibited IL-12 release by human monocytes. The suppression was
selective for IL-12 and occurred after T cell-dependent or -independent
stimulation of monocytes (21). More recently, ligation of
CD47 on human monocyte-derived dendritic cells was shown to inhibit
their activation, cytokine production, and maturation
(22). Here we show that in addition to blocking IL-12
production, CD47 ligation also inhibits the responsiveness to exogenous
IL-12 and the maturation of naive neonatal human T cells into Th1
effectors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Anti-CD3 mAb (UCHT-1) was kindly provided by Dr. P. Beverley (University College Middlesex School of Medicine, London, U.K.). Neutralizing mouse anti-human IL-4 mAb (clone 8F12), rhIL-2, neutralizing anti-IL-12 Ab, and rhIL-12 were kindly provided by C. Heusser (Novartis, Basel, Switzerland), D. Bron (Bordet Institute, Brussels, Belgium), and F. K. Kahn and M. Gately (Hoffmann-La Roche, Nutley, NJ), respectively. rhIL-4 was received from Immunex (Seattle, WA). The CD32 and B7.1 double-transfected mouse L fibroblasts have been described (23). The 4N1K peptide (KRFYVVMWKK) corresponding to the C-terminal domain of TSP and the mutant 4NGG peptide (KRFYGGMWKK) were obtained from Genosys (The Woodlands, TX). Three anti-CD47 mAbs were used in soluble form: clones B6H12 (mouse IgG1; Biosource, Montreal, Quebec, Canada), 10G2 (described in Ref. 21) and 2D3, (received from E. Brown, Washington University, St. Louis, MO). Mouse IgG1 control mAb anti-Rye and anti-CD2 (OKT11) were produced in our laboratory and purchased from American Type Culture Collection (Manassas, VA), respectively. F(ab')2 anti-CD47 mAb fragments were prepared using a commercial kit from Pierce (Brockville, Ontario, Canada).
Cell preparation and culture conditions
Umbilical cord blood mononuclear cells (CBMCs) were isolated by
density gradient centrifugation of heparinized umbilical cord blood
from normal healthy volunteers using Lymphoprep (Nycomed, Oslo,
Norway). CBMCs (1 x 106 cells/ml) were
cultured in triplicate in 24-well culture plates in 1 ml of RPMI 1640
(BioWhittaker, Walkersville, MD) containing 5% FCS, 2 mM
L-glutamine, 50 IU penicillin and 100 µg streptomycin,
and PHA (2 µg). For the induction of Th1 and Th2 polarization, cells
were cultured in the presence of rIL-12 (60 pM) and anti-IL-4 mAb
(1 µg/ml) or a combination of rIL-4 (20 ng/ml) and anti-IL-12 Ab
(5 µg/ml), respectively. After 3 days, cells were washed and cultured
at a starting concentration of 0.5 x 106
cells/ml in culture medium supplemented with 50 U/ml rhIL-2, in 24-well
plates. After 9–12 days of IL-2 culture, cellular expansion in control
cultures was 
35-fold; cells were then washed and 1 x
106 viable T cells/ml were restimulated for
cytokine production with plastic-bound anti-CD3 mAb (10 µg/ml)
alone, plastic-bound anti-CD3 mAb (1 µg/ml) together with soluble
anti-CD28 mAb (clone CD28.2; PharMingen, Ontario, Canada; 2
µg/ml), or anti-CD3 (200 ng/ml) immobilized on irradiated
CD32/B7.1 L cells (2.5 x 105 cells/ml).
Flow cytometric analysis
Cells were stained with FITC- or PE-conjugated mAbs to CD3,
CD25, CD45RA, CD45RO, or isotype-matched controls (Ancell, London,
Ontario, Canada) and analyzed using a FACScan (Becton Dickinson,
Mountain View, CA). To detect intracytoplasmic IFN-, T cells were
stimulated with anti-CD3 mAb immobilized on irradiated CD32/B7.1 L
cells for 6 h in the presence of Monensin (3 mM final
concentration; Hornby, Ontario, Canada). Cells were stained with the
ICScreen Intracellular Staining Kit from Medicorp (Montreal, Quebec,
Canada). IL-12Rß1 and IL-12Rß2 surface expression was assessed
using a three-step procedure. Briefly, cells were first incubated with
anti-IL-12Rß1 mAb (2B10), anti-IL-12Rß2 mAb (2B6), or
class-matched negative control mAb at 2.5 µg/ml in the presence of
normal human IgG (150 µg/ml) for 1 h at 4°C. Cells were then
incubated with biotinylated goat anti-rat IgG (Bio/Can Scientific,
Mississauga, Ontario, Canada) for 1 h at 4°C followed by
PE-labeled streptavidin (Ancell) for 30 min at 4°C. Fas (CD95) and
FasL (CD95L) surface expression was assessed using a two-step
procedure. Cells were first incubated with biotinylated anti-Fas
(M3), biotinylated anti-FasL (NOK-1), or biotinylated class-matched
negative control at 5 to 10 µg/ml in the presence of normal human IgG
(150 µg/ml) for 1 h at 4°C. Cells were then incubated with
PE-labeled streptavidin for 30 min at 4°C. Mean fluorescence
intensity (MFI) was calculated as follows: MFI of sample – MFI of
negative control.
Assay for apoptosis
Phosphatidylserine exposure was done by flow cytometry analysis using a FACScan. Cells were double-stained with 2 µg/ml of FITC-labeled annexin-V (Biodesign International, Kennebunkport, ME) and propidium iodide (PI; Sigma).
Cytokine measurements
IL-2, IL-4, IL-5, IL-10, LT-, TNF-, and IFN- were
measured by two-site sandwich ELISA or RIA exactly as described
(24, 25). At priming, secretion of IL-2 and IFN- was
assessed at 24 h and 72 h, respectively. Unless otherwise
indicated, cytokines were measured after 24 h (IL-2 and IL-4) or
48 h (IFN-, TNF-, LT-, IL-5, and IL-10) of
restimulation.
IL-2 mRNA analysis
CBMCs were collected after 6 h of stimulation in Th1-polarizing conditions in the presence of anti-CD47 mAb or isotype-matched control mAb. Total RNA was prepared with RNeasy Total RNA kit (Qiagen, Chatsworth, CA). Exactly as described (24), 1 µg of RNA from each sample was reversed transcribed by GeneAmp RNA PCR kit from Perkin-Elmer/Cetus (Emeryville, CA) with oligo(dT)16 as the first-strand cDNA primer. Reverse-transcription product (1/20 vol) was mixed with known quantities of serially diluted competitive internal standards (PCR MIMICs; Clontech Laboratories, Palo Alto, CA) and was subjected to quantitative RT-PCR according to the manufacturer’s protocol. Target-specific primer pairs of IL-2 and G3PDH were also purchased from Clontech. After 36 cycles of amplification, the PCR products were resolved on a 1.8% agarose gel containing ethidium bromide. The intensities of competitor-generated bands and the cDNA sample-generated bands determined the quantity of target gene product. The amount of target cDNA was ascertained by determining the amount of competitor required to produce equal molar quantities of target and competitor products. The photographs of agarose gels were further analyzed by computer imaging (NIH Image, version 1.61; National Institutes of Health, Bethesda, MD), and the ratio of the mean histogram of target-generated to competitor-generated bands was calculated. The specificity of the amplified bands was validated by their predicted size.
Statistical analysis
Student’s paired t test was used to determine statistical significance of the data. Values of p < 0.05 were chosen for rejection of the null hypothesis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several positive or negative regulators of IL-12 production
reportedly control IL-12 responsiveness (26, 27, 28, 29, 30). Our
previous report that CD47 down-regulates IL-12 release by APCs
(21, 22) prompted us to evaluate the effect of CD47
ligation on the response of CBMCs to IL-12. CBMCs were activated with
PHA in Th1 (IL-12 + anti-IL-4 mAb) or Th2 (IL-4 + anti-IL-12
Ab) conditions, in the absence or presence of CD47 mAb. Inclusion of
CD47 mAb markedly reduced both IFN- and IL-2 production in Th1
primary cultures without affecting IL-2 production in Th2 primary
cultures (Fig. 1
A). Control
cultures were supplemented with either normal mouse IgG1 or an
irrelevant cell-binding mAb (anti-CD2 mAb). After 3 days of
priming, cells were washed, expanded in IL-2-supplemented medium for 9
to 12 days, washed again, and examined for surface molecule expression
and cytokine production. As depicted in Fig. 1B, regardless
of the priming conditions, virtually all of the cells recovered at the
end of IL-2 expansion were T lymphocytes (CD3+)
displaying the phenotype of newly generated effector cells in that they
were CD45RA+/RO+ and
CD25low. The proportion of CD4/CD8 T cells
(1.6 ± 0.3, n = 4) in this homogenous T cell
population was unaffected by treatment with CD47 mAb. The cellular
viability was uniformly higher than 70% as determined by trypan blue
dye exclusion.
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and no IL-4 at restimulation (Fig. 1
C). Of note,
similar levels of inhibition of IFN- production were observed after
restimulation with plastic-coated anti-CD3 mAb (not shown). Most
interestingly, CD47 ligation in Th2 priming conditions had no effect on
Th2 cell development.
The decrease of IFN- production at priming and restimulation was
CD47 specific and not Fc mediated. As shown in Fig. 2, a CD47-Fc fusion protein containing
the extracellular domain of CD47 completely abrogated the CD47
mAb-mediated inhibition of IFN- production. Furthermore,
F(ab')2 fragments of CD47 mAb as well as the
synthetic peptide 4N1K, corresponding to the CD47 binding site of TSP,
decreased IFN- production almost as efficiently as intact mAb.
Control mutant peptide of TSP had no inhibitory effect (not shown).
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, CD47 mAb added at priming in Th1
conditions suppressed not only IFN- but also TNF- and LT-
production at restimulation. Treatment with CD47 mAb did not affect the
production of IL-4, IL-5, or IL-10, which remained undetectable in
these Th1-promoting culture conditions. The suppressive effect on Th1
development contrasted with the lack of an effect on Th2 cell
development after priming in the presence of exogenous IL-4. Similar
results were obtained by examining cytokine production by
CD4+ T or CD8+ T cells
purified at the end of the IL-2 expansion culture (not shown).
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CD47-mediated inhibition of Th1 effector generation results from impaired IL-12 responsiveness
We next analyzed the possible mechanisms whereby
CD47-treated cells secreted decreased levels of Th1 cytokines. First,
we showed that it did not result from an increase of activation-induced
cell death as measured by FACs analysis of FITC-annexin-and PI-stained
cells before and after anti-CD3 stimulation (Fig. 3A). Note that the 2-fold
increase in annexin+/PI+
CD47-treated cells was not considered to be significant, because it was
not consistently observed in three independent experiments in the
course of a daily kinetic study performed during 9 days of cellular
expansion in IL-2 (not shown). Also, the expression of Fas and FasL
(albeit a low level of expression) was not significantly affected by
CD47 mAb treatment (Fig. 3B). Second, we examined whether
CD47 ligation impaired IL-12 responsiveness at priming. The data in
Fig. 4A revealed that
inclusion of CD47 mAb completely prevented the enhanced production of
IFN- stimulated by IL-12 + anti-IL-4 mAb. Most importantly, the
inhibition of Th1 cell development was confirmed by showing reduced
IFN- production at the single-cell level (Fig. 4B).
Third, we examined whether the CD47-mediated inhibition of IL-12
responsiveness was correlated with down-regulation of IL-12R expression
at the end of the primary cultures. In agreement with previous reports
(9, 10), the expression of IL-12Rß2 was increased in the
presence of IL-12, whereas the constitutive expression of IL-12Rß1
was not enhanced (Fig. 4C). As depicted in the same figure,
CD47 mAb markedly suppressed IL-12Rß2 expression on CBMCs activated
with PHA as well as the enhancing effect of IL-12.
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Exogenous IL-2, added at priming, restores IL-12Rß2 expression and Th1 development of CD47-treated cells
IL-2 reportedly up-regulated IL-12R expression on activated T
cells (6) and, as indicated in Fig. 1A, CD47
mAb suppressed IL-12- but not IL-4-induced IL-2 production in primary
Th1 cultures of CBMCs. The reduced IL-2 secretion was confirmed at the
mRNA level by RT-PCR (Fig. 5A). We therefore examined
whether addition of exogenous IL-2 at priming counteracted CD47
mAb-mediated inhibition of Th1 development. As depicted in Fig. 5, exogenous IL-2 strongly up-regulated IL-12Rß2 expression and
completely prevented CD47 mAb-mediated down-regulation of IL-12Rß2
expression at the end of primary cultures (Fig. 5B) and
IFN- production at priming and restimulation. This effect was dose
dependent (Fig. 5C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Interestingly, most of the molecules inhibiting IL-12 production also suppress IL-12 responsiveness, including IL-4, IL-10, TGF-ß, glucocorticosteroids, PGE2, cholera toxin, adenosine, the compound lisofylline, and 1,25(OH)2 vitamin D3 (8, 26, 27, 28, 29, 30, 41, 42, 43). Ligation of CD47, like 1,25(OH)2 vitamin D3 (44), inhibits Th1 development without inducing a deviation toward Th2. There was no increase of endogenous IL-4 production in that 1) the experiments were conducted in the presence of anti-IL-4 neutralizing mAb and 2) IL-4 remained undetectable. Inhibition of Th1 development is often but not necessarily associated with an induction of Th2 phenotype. For instance, coactivation of naive T cells by anti-CD4 mAb inhibited Th1 differentiation and induced Th2 development (45). Also, IL-12-deficient BALB/c mice, when primed with Ag in CFA, mounted a Th2 instead of a Th1 response. By contrast, IL-12-deficient C57BL/6 mice failed to develop Th1 and Th2 responses, a phenomenon not mediated by endogenous IL-4 or IL-10 (46). A role for endogenous IL-10 in CD47 mAb-mediated inhibition of Th1 response is not supported by the observations that IL-10 was undetectable in primary and secondary cultures and that an anti-IL-10 mAb did not affect CD47 mAb-mediated suppression (data not shown). Our previous reports indicated that the suppression of IL-12 production by CD47 ligation was IL-10 independent (21, 22). Finally, the inhibition of Th1 development by CD47 mAb is selective, given that it has no effect at all on the Th2 response induced by exogenous IL-4.
Most importantly, the inhibition of Th1 development by CD47 mAb is
evidenced by the suppressed production of IFN- at the single-cell
level and a markedly reduced secretion of Th1 cytokines (IFN-,
LT-, and TNF-) at restimulation of primed T cells that have been
expanded for 9 to 12 days in IL-2. In agreement with Rogers et al.
(47), IL-2 promoted the development of effectors as well
as their expansion. Note that almost complete inhibition of Th1
cytokine production was also observed in the absence of intermediate
culture in IL-2 (M.-N. Avice, unpublished data).
The inhibition of IL-12 responsiveness is often associated with
down-regulation of IL-12Rß2 and/or STAT-4 phosphorylation (26, 27). As mentioned, factors regulating the expression of the
IL-12Rß2 subunit play a critical role in Th1 cell development
(6). After TCR-mediated activation, primary T cells
transiently express low levels of IL-12Rß2 that are sufficient to
confer T cell responsiveness to IL-12. The latter up-regulates
IL-12Rß2 by itself and induces IFN - production, which in its turn
induces long-term expression of this receptor at high levels (9, 10). It was recently demonstrated that the initial up-regulation
of IL-12Rß2 after TCR stimulation is strictly dependent on IL-2
production by the activated T cells (48). Thus, in the
absence of this early IL-2 production, activated T cells fail to
respond to IL-12 and subsequently IFN- and cannot acquire a Th1
phenotype, even when primed in the presence of exogenous IL-12 or IFN-
(48).
We here show that ligation of CD47 in primary cultures of mitogen- and
IL-12- activated CBMCs not only inhibits the expression of IL-12Rß2
but also the production of IL-2 and IFN-. We therefore propose that
the selective inhibition of Th1 response results from CD47-mediated
suppression of IL-2 production by activated naive T cells costimulated
with IL-12 but not IL-4 (Fig. 1). Indeed, IL-2 synthesis is suppressed
in primary cultures as determined at the protein and mRNA levels, and
exogenous IL-2 completely reverses all the effects of CD47 mAb, i.e.,
IL-12Rß2 expression, IFN- production, and Th1 cell
differentiation. Note that anti-IL-2 and anti-IL-2R mAbs
suppress IL-12-induced IFN- production to the same extent as
anti-CD47 mAb (M-N. Avice, unpublished observations). These results
are in complete agreement with recent findings in the mouse
demonstrating that early IL-2 production is required for in vitro and
in vivo induction of Th1 response (48) and provide an
explanation to the earlier observations on the critical role of IL-2 in
Th1 cell development (49). Our unpublished data further
indicate that IL-2 could be replaced by IL-15 that was shown to
synergize with IL-12 in inducing IFN- production by T cells
(25, 50). As mentioned, IL-4 completely overrides the CD47
mAb-mediated inhibitory effect. This is not surprising, given that IL-4
and IL-15 utilize the ß and chains of the IL-2R. However, we
cannot rule out the possibility that IL-2 recruits additional
regulatory mechanisms that circumvent the CD47-dependent pathway of
inhibition.
Taken collectively, the present findings underline the immunoregulatory
role of CD47 and its natural ligand TSP. Together with their ability to
inhibit IL-12 production and dendritic cell maturation, our data
support the notion that this pair of receptor-ligand molecules may
function as natural anti-inflammatory and immunosuppressive agents.
TSP is a multifunctional molecule with distinct binding sites for
vß3,
4ß1, and
5ß1 integrins;
immature TGF-ß; CD36; and CD47 (20, 51, 52, 53). It
reportedly enhances the phagocytosis of apoptotic cells, a process that
not only fails to induce inflammation but may even suppress it
(54, 55). In addition, TSP transforms latent TGF-ß into
a very potent anti-inflammatory cytokine, and TSP-deficient animals
display diffuse inflammatory lesions that are corrected by the
administration of TGF-ß (56, 57). Note that
signal-regulatory protein (SIRP), selectively expressed on neuronal and
myeloid cells, was recently described to serve as a novel ligand for
CD47 (58), and we are currently investigating its role in
the regulation of IL-12 response.
Agents capable of blocking IL-12 production and/or responsiveness are therefore potential candidates for the treatment or prevention of Th1 autoimmune diseases (31, 32, 33, 44). For instance, administration of anti-IL-12 mAb but not anti-CD40L mAb (which only decreased IL-12 secretion but not IL-12 responsiveness) completely abrogated established colitis of 4,4,6-trinitrobenzine sulfonic acid-treated mice. Also, 1,25(OH)2 vitamin D3, a potent inhibitor of Th1 response, is an effective treatment of chronic-relapsing experimental allergic encephalomyelitis. Thus, if applicable in vivo, the present findings suggest that inhibiting IL-12-induced IL-2 production and IL-12 responsiveness by targeting CD47 represents a novel and unexplored pathway for the management and prevention of disease-promoting or undesired Th1 responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprints requests to Dr. Marika Sarfati at his current address: Institut Pasteur, 25-28 Dr Roux, Paris 75015, France.
3 Abbreviations used in this paper: LT-, lymphotoxin-, TSP, thrombospondin; CBMC, umbilical cord blood mononuclear cell; MFI, mean fluorescence intensity; PI, propidium iodide; rh, recombinant human.
Received for publication May 12, 2000. Accepted for publication July 27, 2000.
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  G. Fortin, M. Raymond, V. Q. Van, M. Rubio, P. Gautier, M. Sarfati, and D. Franchimont A role for CD47 in the development of experimental colitis mediated by SIRP{alpha}+CD103- dendritic cells J. Exp. Med., August 31, 2009; 206(9): 1995 - 2011. [Abstract] [Full Text] [PDF]
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 L. Lamy, M. Ticchioni, A. K. Rouquette-Jazdanian, M. Samson, M. Deckert, A. H. Greenberg, and A. Bernard CD47 and the 19 kDa Interacting Protein-3 (BNIP3) in T Cell Apoptosis J. Biol. Chem., June 20, 2003; 278(26): 23915 - 23921. [Abstract] [Full Text] [PDF]
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P. P. Manna and W. A. Frazier The Mechanism of CD47-Dependent Killing of T Cells: Heterotrimeric Gi-Dependent Inhibition of Protein Kinase A J. Immunol., April 1, 2003; 170(7): 3544 - 3553. [Abstract] [Full Text] [PDF]
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H. O. Barazi, Z. Li, J. A. Cashel, H. C. Krutzsch, D. S. Annis, D. F. Mosher, and D. D. Roberts Regulation of Integrin Function by CD47 Ligands. DIFFERENTIAL EFFECTS ON alpha vbeta 3 AND alpha 4beta 1 INTEGRIN-MEDIATED ADHESION J. Biol. Chem., November 1, 2002; 277(45): 42859 - 42866. [Abstract] [Full Text] [PDF]
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V. Mateo, E. J. Brown, G. Biron, M. Rubio, A. Fischer, F. L. Deist, and M. Sarfati Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization Blood, September 26, 2002; 100(8): 2882 - 2890. [Abstract] [Full Text] [PDF]
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 Z. Li, M. J. Calzada, J. M. Sipes, J. A. Cashel, H. C. Krutzsch, D. S. Annis, D. F. Mosher, and D. D. Roberts Interactions of thrombospondins with {alpha}4{beta}1 integrin and CD47 differentially modulate T cell behavior J. Cell Biol., April 29, 2002; 157(3): 509 - 519. [Abstract] [Full Text] [PDF]
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H. Yoshida, Y. Tomiyama, K. Oritani, Y. Murayama, J. Ishikawa, H. Kato, J.-i. Miyagawa, N. Honma, T. Nishiura, and Y. Matsuzawa Interaction Between Src Homology 2 Domain Bearing Protein Tyrosine Phosphatase Substrate-1 and CD47 Mediates the Adhesion of Human B Lymphocytes to Nonactivated Endothelial Cells J. Immunol., April 1, 2002; 168(7): 3213 - 3220. [Abstract] [Full Text] [PDF]
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M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati Role of CD47 in the Induction of Human Naive T Cell Anergy J. Immunol., September 1, 2001; 167(5): 2459 - 2468. [Abstract] [Full Text] [PDF]
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S. Latour, H. Tanaka, C. Demeure, V. Mateo, M. Rubio, E. J. Brown, C. Maliszewski, F. P. Lindberg, A. Oldenborg, A. Ullrich, et al. Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-{alpha}: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation J. Immunol., September 1, 2001; 167(5): 2547 - 2554. [Abstract] [Full Text] [PDF]
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Z. Li, M. J. Calzada, J. M. Sipes, J. A. Cashel, H. C. Krutzsch, D. S. Annis, D. F. Mosher, and D. D. Roberts Interactions of thrombospondins with {alpha}4{beta}1 integrin and CD47 differentially modulate T cell behavior J. Cell Biol., April 29, 2002; 157(3): 509 - 519. [Abstract] [Full Text] [PDF]
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