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* Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan;
Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, GM-CSF, or
IL-4, and on DCs by IFN-, GM-CSF, or IL-4. In contrast, B7-DC
expression was only inducible on macrophages and DCs upon stimulation
with IFN-, GM-CSF, or IL-4. The inducible expression of PD-1 ligands
on both T cells and APCs may suggest new paradigms of PD-1-mediated
immune regulation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, two new members of the B7 family, B7-H1 (PD-L1) and B7-DC
(PD-L2), have been identified to be the ligands for PD-1
(10, 11, 12, 13). In vitro studies have shown that the engagement
of PD-1 by B7-H1 or B7-DC inhibited TCR-mediated T cell proliferation
and cytokine production (IFN-, IL-10, IL-4, and IL-2) (11, 12). These results indicated that the cross-linking of PD-1 by
B7-H1 or B7-DC leads to down-regulation of T cell responses. However,
not all studies support the inhibitory role for B7-H1 and B7-DC. Our
previous study has shown that resting T cells stimulated with
immobilized anti-CD3 and B7-DC-Ig exhibited enhanced proliferation
and IFN- production (13). Another group has also
indicated that when T cells were stimulated with low levels of
anti-CD3 and immobilized B7-H1-Ig, proliferation and production of
IFN-, GM-CSF, and IL-10 were enhanced (10, 14). These
results indicated that B7-H1 and B7-DC could costimulate T cell
proliferation and cytokine production. The reason for these
contradictory results remains unknown. One possible explanation may be
the presence of a second receptor for B7-H1 and B7-DC, which delivers a
stimulatory signal. Alternatively, since the ITSM in CD150 has been
implicated in both positive and negative signaling, the ITSM in PD-1
may also be responsible for positive or negative signaling via PD-1
(7).
B7-H1 mRNA was detected in various organs, including the heart, lung,
thymus, spleen, kidney, and liver, and was up-regulated by IFN- in
monocytes and dendritic cells (DCs) (10, 11). B7-DC mRNA
was detected in the liver at a high level and in the lung and spleen at
lower levels and was preferentially expressed in bone marrow-derived
and splenic DCs but not in macrophages (12, 13). These
results suggested the expression of B7-H1 and B7-DC in DCs, which are
critical APCs regulating T cell activation and tolerance. However, the
cell surface expression of B7-H1 and B7-DC on various APC populations
and its regulation remain largely unknown. In this study, we newly
generated mAbs against murine B7-H1 and B7-DC and determined the
expression of PD-1 receptor and ligands on T cells, B cells,
macrophages, and DCs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six-week-old male C57BL/6 and BALB/c mice and 6-wk-old female SD
rats were purchased from Charles River Breeding Laboratories Japan
(Atsugi, Japan). Murine T lymphomas L5178Y, WR19L, EL-4, and
BW5147; B lymphomas A20.2J, LK35.2, and 2PK-3; macrophage cell lines
J774A.1, RAW264.7, and P388D1; melanoma B16; myeloma P3U1
(P3X63Ag8U.1); and Chinese hamster ovary cell line (CHO) were purchased
from American Type Culture Collection (Manassas, VA). The hybridomas
producing mAbs against CD8 (3.155) and Thy1.2 (J1j) were also obtained
from American Type Culture Collection. The hybridoma producing mAb
against CD4 (RL172) was kindly provided by T. Tanaka (Osaka University,
Osaka, Japan). T lymphoma MBL-2 and erythroleukemia FBL-3 were provided
by T. Nishimura (Hokkaido University, Sapporo, Japan). A normal rat
kidney cell line NRK-52E was kindly provided by T. Otsuka (Institute of
Cytosignal Research, Tokyo, Japan). B lymphoma BAL17, renal carcinoma
Renca, fibrosarcoma Meth A, and neuroblastoma C1300 were obtained from
the Japanese Collection of Research Bioresources (Osaka, Japan). These
cells were cultured in RPMI 1640 medium containing 10% FCS, 10 mM
HEPES, 2 mM L-glutamine, 0.1 mg/ml penicillin and
streptomycin, and 50 µM 2-ME. CHO cells were cultured in 
-MEM
medium containing 10% FCS, 10 mM HEPES, 2 mM L-glutamine,
and 0.1 mg/ml penicillin, and streptomycin.
Abs and reagents
Purified anti-CD16/32 (2.4G2) and CD3 (145-2C11) mAbs,
FITC-conjugated anti-CD4 (RM4-4), CD45R/B220 (RA3-6B2), and CD11c
(HL3) mAbs, PE-conjugated anti-CD62L (MEL-14) mAb,
allophycocyanin-conjugated anti-CD8
(7) mAb, biotin-conjugated anti-OX40 (OX86),
CD69 (H1.2F3), CD54 (3E2) mAbs, rat IgG isotype control, hamster IgG
control, and PE-labeled streptavidin were purchased from BD Biosciences
(San Jose, CA). FITC-conjugated F4/80 was purchased from Caltag
Laboratories (Burlingame, CA). Anti-CD40 (HM40-3) and PD-1 (J43) mAbs
were prepared as described previously (2, 15). Anti-CD28
(PV-1) mAb was kindly provided by R. Abe (Science University of Tokyo,
Chiba, Japan). Goat anti-mouse IgM F(ab')2 Ab
was purchased from Jackson ImmunoResearch Laboratories (West Grove,
PA). LPS was purchased from Sigma-Aldrich (St. Louis, MO). Recombinant
mouse GM-CSF, IL-4, IL-12, and IFN- were purchased from BD
Biosciences.
Preparation of mouse B7-H1 and B7-DC transfectants
A cDNA fragment encoding the entire open reading frame of mouse B7-H1 was prepared by RT-PCR from BALB/c peritoneal macrophages. A 5'-CCGCTCGAGCCCAAAACATGAGGATATTTG-3' corresponding to nt 9–28 of murine B7-H1 cDNA (11) tagged with an XhoI site and 5'-ATAAGAATGCGGCCGCTTACGTCTCCTCGAATTGTG-3' corresponding to nt 870–889 tagged with a NotI site were used as 5' and 3' primers, respectively. The PCR product was cloned into a pMKITneo vector, kindly provided by K. Maruyama (Tokyo Medical and Dental University, Tokyo, Japan), and transfected into CHO cells with Lipofectin (Invitrogen, Carlsbad, CA) and into L5178Y and NRK by electroporation. After selection by 1 mg/ml geneticin (Sigma-Aldrich), transfectants stably expressing B7-H1 were identified by staining with PD-1-Ig fusion protein consisting of the extracellular portion of mouse PD-1 (aa 124–564) (1) and the Fc portion of human IgG1. Mouse B7-DC cDNA cloned into a pCAGGS expression vector (13) was transfected into CHO cells with Lipofectin and into RAW264.7, L5178Y, and NRK by electroporation. After selection by 8 µg/ml blasticidin (Invitrogen), transfectants stably expressing B7-DC were identified by staining with PD-1-Ig.
Generation of anti-mouse B7-H1 and B7-DC mAbs
To prepare anti-mouse B7-H1 and B7-DC mAbs, SD rats were
immunized with B7-H1-transfected L5178Y or B7-DC-transfected RAW264.7
cells. Three days after the final immunization, spleen cells or lymph
node cells were fused with P3U1 myeloma cells. After
hypoxanthine-aminopterin-thymidine selection, a hybridoma (MIH6, rat
IgG2a/
) producing anti-B7-H1 mAb and a hybridoma (TY25, rat
IgG2a/
) producing anti-B7-DC mAb were selected by their strong
reactivity to B7-H1-transfected CHO or B7-DC-transfected NRK, but not
to parental cells by flow cytometry and then cloned by limiting
dilution. Both MIH6 and TY25 were purified from ascites by the caprylic
acid and ammonium sulfate precipitation method, and purity was verified
by SDS-PAGE analysis.
Immunoprecipitation and Western blotting
Cells (1 x 107) were lysed in 1 ml of a lysis buffer containing 1% Nonidet P-40, 50 mM HEPES (pH 7.4), 250 mM NaCl, and 2 mM EDTA. Cellular debris and nuclei were removed by centrifugation, and the supernatant was precleared with protein G-Sepharose (Amersham Biosciences, Piscataway, NJ) preincubated with control rat IgG2a for 3 h at 4°C. The cleared lysates were immunoprecipitated with MIH6-preloaded, TY25-preloaded, or control rat IgG2a-preloaded protein G-Sepharose for 1 h at 4°C. The beads were washed three times with the lysis buffer, and bound proteins were eluted with 1% SDS sample buffer, subjected to 10% SDS-PAGE, and then blotted onto polyvinylidene difluoride membrane (Millipore, Bedford, MA). The blotted proteins were detected using biotin-conjugated MIH6, TY25, or rat IgG2a followed by avidin-biotinylated peroxidase complex (Vector Laboratories, Burlingame, CA) and an ECL Western Blotting Detection System (Amersham Biosciences) according to the manufacturer’s instructions.
RT-PCR
Total RNA was extracted from cell lines (1 x
107) using RNA STAT-60 (Tel-Test, Friendswood,
TX). First-strand cDNA was prepared using a SuperScript First-Strand
Synthesis System (Invitrogen) from 5 µg of total RNA. cDNA samples
were standardized based on the content of 
-actin cDNA. Primers for
mouse -actin were 5'-GTGGGCCGCTCTAGGCACCAA-3' and
5'-CTCTTTGATGTCACGCACGATTTC-3'. Primers for mouse B7-H1 were
5'-ATGAGGATATTTGCTGGCATTAT-3' and 5'-TTACGTCTCCTCGAATTGTGT-3'. Primers
for mouse B7-DC were 5'-ATGCTGCTCCTGCCCTGCCG-3' and
5'-CTAGATCCTCTTTCTCTGGAT-3'. PCR was performed in a total volume of
20 µl in PCR buffer in the presence of 0.2 mM dNTP, 1 µM of each
primer, and 1 U of Taq DNA polymerase (Advanced
Biotecnologies, Surrey, U.K.). After 35 cycles of amplification, the
PCR products were separated by electrophoresis on a 2% agarose gel and
visualized by ethidium bromide staining.
Preparation and stimulation of T cells, B cells, and macrophages
CD4+CD62L+
naive T cells were purified from the spleen of C57BL/6 mice by passage
through nylon wool columns (Wako Biochemicals, Osaka, Japan) and by
using an auto-MACS column with FITC-conjugated anti-CD4,
anti-FITC multisort kit, and anti-CD62L-coupled microbeads
(Miltenyi Biotec, Bergisch Gladbach, Germany) according to the
manufacturer’s instructions. Purified naive CD4 T cells (3 x
106/ml; >95%
CD4+CD62L+) were
stimulated with immobilized anti-CD3 mAb (5 µg/ml) in the
presence or absence of anti-CD28 mAb (3 µg/ml) for 24–96 h.
Small resting B cells were purified as previously described
(16). Briefly, splenocytes from C57BL/6 mice were treated
with a mixture of hybridoma supernatants (anti-Thy-1.2,
anti-CD4, and anti-CD8) and Low-Tox rabbit complement
(Cedarlane Laboratories, Hornby, Ontario, Canada). After Percoll
(Amersham Biosciences) gradient centrifugation, small B cells were
collected from the 60/70% interface. Purified B cells (3 x
106/ml; >95% B220+) were
stimulated with anti-IgM Ab (5 µg/ml) and/or anti-CD40 mAb
(10 µg/ml), or LPS (5 µg/ml) for 24–72 h. Peritoneal macrophages
were obtained from C57BL/6 mice that received i.p. 2 ml of 4%
thioglycolate (Sigma-Aldrich) 4 days before. Peritoneal exudate cells
were harvested by peritoneal lavage with ice-cold PBS and depleted of
nonadherent cells after a 1-h culture on a plastic dish, and then
stimulated with anti-CD40 mAb (5 µg/ml), LPS (5 µg/ml), GM-CSF
(10 ng/ml), IL-4 (20 ng/ml), or IFN- (20 ng/ml) for 24–72
h.
Preparation of bone marrow-derived DCs and splenic DCs
Bone marrow-derived DCs (BMDCs) were prepared by culturing bone
marrow cells (5 x 105/ml) from C57BL/6 mice
in the presence of GM-CSF (10 ng/ml) for 4–8 days. Nonadherent cells
were removed from the culture and fresh medium containing GM-CSF was
fed at days 2, 4, and 6 after the initiation of culture. For isolating
splenic DCs, spleens from C57BL/6 mice were digested with 400 U/ml
collagenase (Wako Biochemicals) in the presence of 5 mM EDTA and
separated into low- and high-density fractions on an Optiprep gradient
(Axis-Shield, Oslo, Norway). Low-density cells were incubated with
anti-CD11c-coupled magnetic beads and the bound cells were isolated
by the auto-MACS column. The purified splenic DCs (2 x
106/ml; >95% CD11c+) were
cultured with or without anti-CD40 mAb (5 µg/ml), GM-CSF (10
ng/ml), IL-4 (20 ng/ml), IFN- (20 ng/ml), or IL-12 (10 ng/ml) at
37°C for 24–72 h.
Flow cytometric analysis
Cells (0.5–1 x 106) were first
preincubated with unlabeled anti-CD16/32 mAb to avoid nonspecific
binding of Abs to FcR and then incubated with FITC- or
allophycocyanin-labeled mAbs or biotinylated mAb. After washing with
PBS twice, the cells were incubated with PE-labeled streptavidin for
biotinylated mAb. After washing with PBS twice, the stained cells
(live-gated on the basis of forward and side scatter profiles and
propidium iodide exclusion) were analyzed on a FACSCalibur (BD
Biosciences), and data were processed using the CellQuest program (BD
Biosciences).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To characterize the expression of mouse B7-H1 and B7-DC, we newly
generated specific mAbs. The expression vectors containing mouse B7-H1
or B7-DC cDNA were transfected into L5178Y, RAW264.7, NRK-52E, and CHO
cells. Cell surface expression of B7-H1 and B7-DC on stable
transfectants was verified by staining with PD-1-Ig fusion protein
(data not shown). We immunized SD rats with B7-H1/L5178Y or
B7-DC/RAW264.7 cells and screened the hybridomas producing mAb that
reacted with B7-H1 or B7-DC transfectants but not parental cells. Two
mAbs, designated MIH6 and TY25, were selected. As represented in Fig. 1
, MIH6 reacted strongly with
B7-H1-transfected cells (B7-H1/NRK, B7-H1/CHO, and B7-H1/L5178Y) but
not with B7-DC-transfected or parental NRK and CHO cells. Parental and
B7-DC-transfected L5178Y cells were also stained with MIH6 weakly,
which reflected a low level of endogenous B7-H1 expression in L5178Y
cells (see below). TY25 only reacted with B7-DC-transfected cells
(B7-DC/NRK, B7-DC/CHO, and B7-DC/L5178Y) but not with B7-H1-transfected
cells or parental cells.
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, MIH6
precipitated a 43-kDa protein from B7-H1/L5178Y cells and TY25
precipitated a 42-kDa protein from B7-DC/L178Y cells. The 43-kDa band
was also detected in the MIH6 precipitates from L5178Y and B7-DC/L5178Y
cells after a longer exposure, which appeared to represent endogenously
expressed B7-H1 in L5178Y cells (data not shown).
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We first examined the correlation between the B7-H1 and B7-DC mRNA
expression and the MIH6 and TY25 reactivity in mouse tumor cell lines.
As shown in Fig. 3A, MIH6
reacted with all tested cell lines which expressed B7-H1 mRNA as
estimated by RT-PCR (Fig. 3B). TY25 reacted with MBL-2,
BAL17, and RAW264.7 cells which expressed B7-DC mRNA, but not with the
other cell lines which did not express B7-DC mRNA (Fig. 3). The strict
correlation between the B7-H1 and B7-DC mRNA expression and the MIH6
and TY25 reactivity further substantiated their specificity for B7-H1
and B7-DC.
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We next examined the expression of B7-H1, B7-DC, and PD-1 on
splenic T cells by flow cytometric analysis using MIH6, TY25, and an
anti-mouse PD-1 mAb (J43) we previously generated (2).
An anti-OX40 mAb was also included as an activation marker.
Purified naive CD4+ T cells were stimulated with
immobilized anti-CD3 mAb in the presence or absence of soluble
anti-CD28 mAb for 24–96 h. As shown in Fig. 4A, PD-1 expression was
detected on CD4+ T cells after stimulation with
anti-CD3 mAb alone, which appeared at 24 h and reached a peak
at 48 h. Unexpectedly, naive CD4+ T cells
constitutively expressed B7-H1, which was markedly up-regulated by
stimulation with anti-CD3 mAb alone (Fig. 4A). In
contrast, B7-DC expression was not found on freshly isolated naive
CD4+ T cells, but was marginally detectable after
stimulation with anti-CD3 mAb for 72–96 h (Fig. 4A).
Although the addition of anti-CD28 mAb slightly increased the
expression of both B7-H1 and B7-DC on anti-CD3-stimulated T cells,
it accelerated the reduction of PD-1 expression at 72–96 h (Fig. 4B). Similar patterns of B7-H1, B7-DC, and PD-1 expression
were observed when naive CD8+ T cells were
stimulated with anti-CD3 mAb in the presence or absence of
anti-CD28 mAb (data not shown).
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We next examined the expression of B7-H1, B7-DC, and PD-1 on
splenic B cells. Small resting B cells were stimulated with
anti-IgM Ab, anti-CD40 mAb, both anti-IgM Ab and
anti-CD40 mAb, or LPS for 24–72 h and stained with MIH6, TY25, or
J43. An anti-CD69 mAb was also included as an activation marker.
Expression of PD-1 was found on anti-IgM- or LPS-stimulated B
cells, which was apparent at 48 or 72 h, respectively (Fig. 5, A and D). The
combination of anti-IgM Ab and anti-CD40 mAb markedly induced
the PD-1 expression (Fig. 5C), whereas the stimulation with
anti-CD40 mAb alone was not effective (Fig. 5B). B7-H1
was found on freshly isolated B cells at a substantial level and was
slightly up-regulated by stimulation with anti-IgM Ab (Fig. 5A) or LPS (Fig. 5D) but not with anti-CD40
mAb (Fig. 5, B and C). In contrast, B7-DC was not
found on splenic B cells after any stimulation.
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We also examined the expression of B7-H1, B7-DC, and PD-1 on
thioglycolate-elicited peritoneal macrophages. Purified macrophages
were stimulated with anti-CD40 mAb, LPS, or cytokines (GM-CSF,
IL-4, or IFN-) for 24–72 h. Expression of CD54 was also monitored
as an activation maker. As shown in Fig. 6A, a substantial level of
B7-H1 expression was found on freshly isolated macrophages, which was
increased by 24–48 h culture in medium alone and further up-regulated
by stimulation with LPS, GM-CSF, IL-4, or IFN- (Fig. 6, C--F). Although B7-DC expression was not found on
freshly isolated macrophages (Fig. 6A), it was induced by
stimulation with GM-CSF, IFN-, and especially IL-4 (Fig. 6, D–F). In contrast, PD-1 expression was not found on
macrophages after any stimulation (Fig. 6).
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We previously observed that B7-DC mRNA was preferentially
expressed in BMDCs (13). We now examined the cell surface
expression of B7-H1 and B7-DC on BMDCs, which were prepared by
culturing bone marrow cells with GM-CSF for 4, 6, and 8 days by
staining with MIH6 and TY25 mAbs. As shown in Fig. 7, both B7-H1 and B7-DC were found on
CD11c+ BMDCs from days 4 to 8 of the culture.
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, or IL-12) for 24–48 h. CD69 was also included as an
activation marker. As shown in Fig. 8A, while freshly isolated
CD11c+CD8- DCs expressed
B7-H1 at a higher level than freshly isolated
CD11c+CD8+ DCs, both DC
populations up-regulated the B7-H1 expression to a similar level after
the culture in medium alone for 24 h. The stimulation with
anti-CD40 mAb and cytokines (GM-CSF, IL-4, IFN-, and IL-12)
slightly enhanced the B7-H1 expression (Fig. 8, B–F). In
contrast, B7-DC was not found on freshly isolated DCs, but was induced
at a low level by culture in medium alone (Fig. 8A). The
B7-DC expression was markedly increased by stimulation with GM-CSF,
IL-4, and IFN- on both
CD11c+CD8+ and
CD11c+CD8- DCs (Fig. 8, C–E). Expression of PD-1 was not found on either
CD11c+CD8+ or
CD11c+CD8- DCs even after
stimulation (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been reported that B7-H1 mRNA was broadly expressed whereas B7-DC mRNA was rather restricted in mouse tumor cell lines (12, 13). Consistently, our results demonstrated that cell surface expression of B7-H1 was broadly found on both hemopoietic and nonhemopoietic tumors, but that of B7-DC was restricted to certain leukemias. The engagement of PD-1 by B7-H1 or B7-DC has been reported to inhibit TCR/CD3-mediated T cell proliferation and cytokine production (11, 12, 17). Moreover, Dong et al. (18) recently reported that B7-H1 expressed on tumor cells promoted T cell apoptosis. Therefore, the expression of B7-H1 and B7-DC on tumor cells may represent a novel tumor escape mechanism from immunosurveillance.
Using flow cytometric analysis, we formally determined the expression of B7-H1, B7-DC, and PD-1 on murine T cells and APCs including B cells, macrophages, and DCs. Some new findings were obtained as follows.
Our previous report demonstrated the PD-1 expression on splenic T cells after anti-CD3, Con A, or PMA plus ionomycin stimulation (2). We now demonstrated that PD-1 could be expressed on naive T cells upon anti-CD3 stimulation alone without anti-CD28 costimulation. More importantly, B7-H1 is constitutively expressed on naive T cells and markedly up-regulated by anti-CD3 stimulation. It has been known that TCR/CD3 stimulation of naive T cells in the absence of CD28 costimulation induces anergy (19). PD-1-B7-H1 interaction may be involved in this process.
On splenic B cells, PD-1 expression was induced by anti-IgM or PMA plus ionomycin stimulation (2). We here demonstrated a higher expression of PD-1 by anti-IgM plus anti-CD40 stimulation and no induction by anti-CD40 stimulation alone. This suggests that PD-1 is preferentially expressed on surface Ig-stimulated Ag-specific B cells upon interaction with CD40L-expressing Th cells. PD-1-/- C57BL/6 mice developed lupus-like disease with and increased number of B cells and serum IgG2b, IgG3, and IgA (20). PD-1-/- BALB/c mice developed dilated cardiomyopathy with a high level of IgG1 autoantibodies (9). These studies suggested a critical role for PD-1 as a negative regulator of B cell responses. In this respect, our present finding of PD-1 on activated B cells and B7-H1 on activated T cells is intriguing, since it suggests that the engagement of PD-1 on B cells by B7-H1 on T cells may constitute a novel pathway of T cell-mediated B cell suppression.
In human monocytes, induction of both B7-H1 and B7-DC mRNAs
by IFN- stimulation has been reported (11, 12). We now
demonstrated that B7-H1 is constitutively expressed on the surface of
murine peritoneal macrophages and is up-regulated by LPS, IFN-, and
IL-4. In addition, B7-DC expression was also induced by GM-CSF,
IFN-, and IL-4. These results indicated that B7-H1 and B7-DC
expression on macrophages can be regulated by both Th1 (IFN- and
GM-CSF) and Th2 (IL-4) cytokines. Further studies are now under way to
explore the costimulatory or suppressive function of B7-H1 and B7-DC on
macrophages when they act as APCs for T cells.
We previously demonstrated that B7-DC mRNA was preferentially expressed
in BMDCs but not in bone marrow-derived macrophages (13).
We now verified the cell surface expression of B7-DC, as well as B7-H1,
on BMDCs. This B7-DC expression on BMDCs seems to result from GM-CSF
stimulation rather than differentiation into DCs, as observed with
peritoneal macrophages. Among freshly isolated splenic DCs, the
CD8- myeloid DC population exhibited a higher
expression of B7-H1 than the CD8+ lymphoid DC
population, mechanisms for which are presently unknown. However, both
DC populations rapidly up-regulated B7-H1 expression to a similar level
upon in vitro culture, which may be mediated by autocrine GM-CSF.
Although we previously showed the expression of B7-DC mRNA in splenic
DCs (13), cell surface expression of B7-DC was not found
on freshly isolated splenic DCs but was rapidly induced upon in vitro
culture, which may be also induced by autocrine GM-CSF. Alternatively,
cell surface expression of B7-DC on splenic DCs may be
posttranscriptionally modulated in situ. B7-H1 and B7-DC expression on
splenic DCs was further up-regulated by both Th1 (IFN- and GM-CSF)
and Th2 (IL-4) cytokines. This may be relevant to the costimulation or
suppression of both Th1 and Th2 responses by these molecules.
In summary, we herein characterized the cell surface expression of B7-H1 and B7-DC on murine T cells and APCs including B cells, macrophages, and DCs. Further studies are required to explore the functional roles of B7-H1 and B7-DC on these cells. The regulated expression of these two PD-1 ligands on both T cells and APCs suggest new paradigms of PD-1-mediated immune regulation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hideo Yagita, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: hyagita{at}med.juntendo.ac.jp
3 Abbreviations used in this paper: PD-1, programmed death 1; ITSM, immunoreceptor tyrosine-based switch motif; DC, dendritic cell; CHO, Chinese hamster ovary; BMDC, bone-marrow derived DC.
Received for publication August 1, 2002. Accepted for publication September 3, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L. J. Robays, E. A. Lanckacker, K. B. Moerloose, T. Maes, K. R. Bracke, G. G. Brusselle, G. F. Joos, and K. Y. Vermaelen Concomitant Inhalation of Cigarette Smoke and Aerosolized Protein Activates Airway Dendritic Cells and Induces Allergic Airway Inflammation in a TLR-Independent Way J. Immunol., August 15, 2009; 183(4): 2758 - 2766. [Abstract] [Full Text] [PDF]
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 S. Sugita, Y. Usui, S. Horie, Y. Futagami, H. Aburatani, T. Okazaki, T. Honjo, M. Takeuchi, and M. Mochizuki T-Cell Suppression by Programmed Cell Death 1 Ligand 1 on Retinal Pigment Epithelium during Inflammatory Conditions Invest. Ophthalmol. Vis. Sci., June 1, 2009; 50(6): 2862 - 2870. [Abstract] [Full Text] [PDF]
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 M. Nikolova, J.-D. Lelievre, M. Carriere, A. Bensussan, and Y. Levy Regulatory T cells differentially modulate the maturation and apoptosis of human CD8+ T-cell subsets Blood, May 7, 2009; 113(19): 4556 - 4565. [Abstract] [Full Text] [PDF]
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T. W. Phares, C. Ramakrishna, G. I. Parra, A. Epstein, L. Chen, R. Atkinson, S. A. Stohlman, and C. C. Bergmann Target-Dependent B7-H1 Regulation Contributes to Clearance of Central Nervous Sysyem Infection and Dampens Morbidity J. Immunol., May 1, 2009; 182(9): 5430 - 5438. [Abstract] [Full Text] [PDF]
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 X. Huang, F. Venet, Y. L. Wang, A. Lepape, Z. Yuan, Y. Chen, R. Swan, H. Kherouf, G. Monneret, C.-S. Chung, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis PNAS, April 14, 2009; 106(15): 6303 - 6308. [Abstract] [Full Text] [PDF]
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V. V. Parekh, S. Lalani, S. Kim, R. Halder, M. Azuma, H. Yagita, V. Kumar, L. Wu, and L. Van Kaer PD-1/PD-L Blockade Prevents Anergy Induction and Enhances the Anti-Tumor Activities of Glycolipid-Activated Invariant NKT Cells J. Immunol., March 1, 2009; 182(5): 2816 - 2826. [Abstract] [Full Text] [PDF]
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 B. Li, M. VanRoey, C. Wang, T.-h. T. Chen, A. Korman, and K. Jooss Anti-Programmed Death-1 Synergizes with Granulocyte Macrophage Colony-Stimulating Factor-Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors Clin. Cancer Res., March 1, 2009; 15(5): 1623 - 1634. [Abstract] [Full Text] [PDF]
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E. D. Reynoso, K. G. Elpek, L. Francisco, R. Bronson, A. Bellemare-Pelletier, A. H. Sharpe, G. J. Freeman, and S. J. Turley Intestinal Tolerance Is Converted to Autoimmune Enteritis upon PD-1 Ligand Blockade J. Immunol., February 15, 2009; 182(4): 2102 - 2112. [Abstract] [Full Text] [PDF]
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A.-Y. Gong, R. Zhou, G. Hu, X. Li, P. L. Splinter, S. P. O'Hara, N. F. LaRusso, G. A. Soukup, H. Dong, and X.-M. Chen MicroRNA-513 Regulates B7-H1 Translation and Is Involved in IFN-{gamma}-Induced B7-H1 Expression in Cholangiocytes J. Immunol., February 1, 2009; 182(3): 1325 - 1333. [Abstract] [Full Text] [PDF]
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W.-S. Chang, J.-Y. Kim, Y.-J. Kim, Y.-S. Kim, J.-M. Lee, M. Azuma, H. Yagita, and C.-Y. Kang Cutting Edge: Programmed Death-1/Programmed Death Ligand 1 Interaction Regulates the Induction and Maintenance of Invariant NKT Cell Anergy J. Immunol., November 15, 2008; 181(10): 6707 - 6710. [Abstract] [Full Text] [PDF]
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Y. S. Kim, G. B. Park, H.-K. Lee, H. Song, I.-H. Choi, W. J. Lee, and D. Y. Hur Cross-Linking of B7-H1 on EBV-Transformed B Cells Induces Apoptosis through Reactive Oxygen Species Production, JNK Signaling Activation, and fasL Expression J. Immunol., November 1, 2008; 181(9): 6158 - 6169. [Abstract] [Full Text] [PDF]
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O. Nagashima, N. Harada, Y. Usui, T. Yamazaki, H. Yagita, K. Okumura, K. Takahashi, and H. Akiba B7-H3 Contributes to the Development of Pathogenic Th2 Cells in a Murine Model of Asthma J. Immunol., September 15, 2008; 181(6): 4062 - 4071. [Abstract] [Full Text] [PDF]
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F. Haspot, T. Fehr, C. Gibbons, G. Zhao, T. Hogan, T. Honjo, G. J. Freeman, and M. Sykes Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway Blood, September 1, 2008; 112(5): 2149 - 2155. [Abstract] [Full Text] [PDF]
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E. Lazar-Molnar, Q. Yan, E. Cao, U. Ramagopal, S. G. Nathenson, and S. C. Almo From the Cover: Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2 PNAS, July 29, 2008; 105(30): 10483 - 10488. [Abstract] [Full Text] [PDF]
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L. Wang, K. Pino-Lagos, V. C. de Vries, I. Guleria, M. H. Sayegh, and R. J. Noelle Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells PNAS, July 8, 2008; 105(27): 9331 - 9336. [Abstract] [Full Text] [PDF]
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C. A. Benedict, A. Loewendorf, Z. Garcia, B. R. Blazar, and E. M. Janssen Dendritic Cell Programming by Cytomegalovirus Stunts Naive T Cell Responses via the PD-L1/PD-1 Pathway J. Immunol., April 1, 2008; 180(7): 4836 - 4847. [Abstract] [Full Text] [PDF]
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 K. A. Green, T. Okazaki, T. Honjo, W. J. Cook, and W. R. Green The Programmed Death-1 and Interleukin-10 Pathways Play a Down-Modulatory Role in LP-BM5 Retrovirus-Induced Murine Immunodeficiency Syndrome J. Virol., March 1, 2008; 82(5): 2456 - 2469. [Abstract] [Full Text] [PDF]
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 K. L. Edgtton, J. Y. Kausman, M. Li, K. O'Sullivan, C. Lo, P. Hutchinson, H. Yagita, S. R. Holdsworth, and A. R. Kitching Intrarenal Antigens Activate CD4+ Cells via Co-stimulatory Signals from Dendritic Cells J. Am. Soc. Nephrol., March 1, 2008; 19(3): 515 - 526. [Abstract] [Full Text] [PDF]
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J. Menke, J. A. Lucas, G. C. Zeller, M. E. Keir, X. R. Huang, N. Tsuboi, T. N. Mayadas, H. Y. Lan, A. H. Sharpe, and V. R. Kelley Programmed Death 1 Ligand (PD-L) 1 and PD-L2 Limit Autoimmune Kidney Disease: Distinct Roles J. Immunol., December 1, 2007; 179(11): 7466 - 7477. [Abstract] [Full Text] [PDF]
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T. Pentcheva-Hoang, L. Chen, D. M. Pardoll, and J. P. Allison Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability PNAS, November 6, 2007; 104(45): 17765 - 17770. [Abstract] [Full Text] [PDF]
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 S.-J. Lin, C. D. Peacock, K. Bahl, and R. M. Welsh Programmed death-1 (PD-1) defines a transient and dysfunctional oligoclonal T cell population in acute homeostatic proliferation J. Exp. Med., October 1, 2007; 204(10): 2321 - 2333. [Abstract] [Full Text] [PDF]
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S. Gaudreau, C. Guindi, M. Menard, G. Besin, G. Dupuis, and A. Amrani Granulocyte-Macrophage Colony-Stimulating Factor Prevents Diabetes Development in NOD Mice by Inducing Tolerogenic Dendritic Cells that Sustain the Suppressive Function of CD4+CD25+ Regulatory T Cells J. Immunol., September 15, 2007; 179(6): 3638 - 3647. [Abstract] [Full Text] [PDF]
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L. Shen, Y. Jin, G. J. Freeman, A. H. Sharpe, and M. R. Dana The Function of Donor versus Recipient Programmed Death-Ligand 1 in Corneal Allograft Survival J. Immunol., September 15, 2007; 179(6): 3672 - 3679. [Abstract] [Full Text] [PDF]
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F. Tsushima, S. Yao, T. Shin, A. Flies, S. Flies, H. Xu, K. Tamada, D. M. Pardoll, and L. Chen Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy Blood, July 1, 2007; 110(1): 180 - 185. [Abstract] [Full Text] [PDF]
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M. R. Nazareth, L. Broderick, M. R. Simpson-Abelson, R. J. Kelleher Jr., S. J. Yokota, and R. B. Bankert Characterization of Human Lung Tumor-Associated Fibroblasts and Their Ability to Modulate the Activation of Tumor-Associated T Cells J. Immunol., May 1, 2007; 178(9): 5552 - 5562. [Abstract] [Full Text] [PDF]
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R. H. Thompson, H. Dong, C. M. Lohse, B. C. Leibovich, M. L. Blute, J. C. Cheville, and E. D. Kwon PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma Clin. Cancer Res., March 15, 2007; 13(6): 1757 - 1761. [Abstract] [Full Text] [PDF]
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H. Maier, M. Isogawa, G. J. Freeman, and F. V. Chisari PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver J. Immunol., March 1, 2007; 178(5): 2714 - 2720. [Abstract] [Full Text] [PDF]
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N. Martin-Orozco, Y.-H. Wang, H. Yagita, and C. Dong Cutting Edge: Programed Death (PD) Ligand-1/PD-1 Interaction Is Required for CD8+ T Cell Tolerance to Tissue Antigens J. Immunol., December 15, 2006; 177(12): 8291 - 8295. [Abstract] [Full Text] [PDF]
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B. T. Fife, I. Guleria, M. Gubbels Bupp, T. N. Eagar, Q. Tang, H. Bour-Jordan, H. Yagita, M. Azuma, M. H. Sayegh, and J. A. Bluestone Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway J. Exp. Med., November 27, 2006; 203(12): 2737 - 2747. [Abstract] [Full Text] [PDF]
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K. M. Hargadon, C. C. Brinkman, S. L. Sheasley-O'Neill, L. A. Nichols, T. N. J. Bullock, and V. H. Engelhard Incomplete Differentiation of Antigen-Specific CD8 T Cells in Tumor-Draining Lymph Nodes J. Immunol., November 1, 2006; 177(9): 6081 - 6090. [Abstract] [Full Text] [PDF]
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Q. Meng, P. Yang, B. Li, H. Zhou, X. Huang, L. Zhu, Y. Ren, and A. Kijlstra CD4+PD-1+ T Cells Acting as Regulatory Cells during the Induction of Anterior Chamber-Associated Immune Deviation. Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4444 - 4452. [Abstract] [Full Text] [PDF]
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G. Iezzi, A. Boni, E. Degl'Innocenti, M. Grioni, M. T. S. Bertilaccio, and M. Bellone Type 2 Cytotoxic T Lymphocytes Modulate the Activity of Dendritic Cells Toward Type 2 Immune Responses J. Immunol., August 15, 2006; 177(4): 2131 - 2137. [Abstract] [Full Text] [PDF]
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Y. Zhang, Y. Chung, C. Bishop, B. Daugherty, H. Chute, P. Holst, C. Kurahara, F. Lott, N. Sun, A. A. Welcher, et al. Regulation of T cell activation and tolerance by PDL2 PNAS, August 1, 2006; 103(31): 11695 - 11700. [Abstract] [Full Text] [PDF]
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A. H. Lau, M. Abe, and A. W. Thomson Ethanol affects the generation, cosignaling molecule expression, and function of plasmacytoid and myeloid dendritic cell subsets in vitro and in vivo J. Leukoc. Biol., May 1, 2006; 79(5): 941 - 953. [Abstract] [Full Text] [PDF]
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M. E. Keir, S. C. Liang, I. Guleria, Y. E. Latchman, A. Qipo, L. A. Albacker, M. Koulmanda, G. J. Freeman, M. H. Sayegh, and A. H. Sharpe Tissue expression of PD-L1 mediates peripheral T cell tolerance J. Exp. Med., April 17, 2006; 203(4): 883 - 895. [Abstract] [Full Text] [PDF]
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H. K. Kim, H. Guan, G. Zu, H. Li, L. Wu, X. Feng, C. Elmets, Y. Fu, and H. Xu High-level expression of B7-H1 molecules by dendritic cells suppresses the function of activated T cells and desensitizes allergen-primed animals J. Leukoc. Biol., April 1, 2006; 79(4): 686 - 695. [Abstract] [Full Text] [PDF]
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B. Zhu, I. Guleria, A. Khosroshahi, T. Chitnis, J. Imitola, M. Azuma, H. Yagita, M. H. Sayegh, and S. J. Khoury Differential Role of Programmed Death-Ligand 1 and Programmed Death-Ligand 2 in Regulating the Susceptibility and Chronic Progression of Experimental Autoimmune Encephalomyelitis J. Immunol., March 15, 2006; 176(6): 3480 - 3489. [Abstract] [Full Text] [PDF]
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S. Das, G. Suarez, E. J. Beswick, J. C. Sierra, D. Y. Graham, and V. E. Reyes Expression of B7-H1 on Gastric Epithelial Cells: Its Potential Role in Regulating T Cells during Helicobacter pylori Infection. J. Immunol., March 1, 2006; 176(5): 3000 - 3009. [Abstract] [Full Text] [PDF]
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N. Cohen, E. Mouly, H. Hamdi, M.-C. Maillot, M. Pallardy, V. Godot, F. Capel, A. Balian, S. Naveau, P. Galanaud, et al. GILZ expression in human dendritic cells redirects their maturation and prevents antigen-specific T lymphocyte response Blood, March 1, 2006; 107(5): 2037 - 2044. [Abstract] [Full Text] [PDF]
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A. L. Neild, S. Shin, and C. R. Roy Activated Macrophages Infected with Legionella Inhibit T Cells by Means of MyD88-Dependent Production of Prostaglandins J. Immunol., December 15, 2005; 175(12): 8181 - 8190. [Abstract] [Full Text] [PDF]
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T. Yamazaki, H. Akiba, A. Koyanagi, M. Azuma, H. Yagita, and K. Okumura Blockade of B7-H1 on Macrophages Suppresses CD4+ T Cell Proliferation by Augmenting IFN-{gamma}-Induced Nitric Oxide Production J. Immunol., August 1, 2005; 175(3): 1586 - 1592. [Abstract] [Full Text] [PDF]
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I. Guleria, A. Khosroshahi, M. J. Ansari, A. Habicht, M. Azuma, H. Yagita, R. J. Noelle, A. Coyle, A. L. Mellor, S. J. Khoury, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance J. Exp. Med., July 18, 2005; 202(2): 231 - 237. [Abstract] [Full Text] [PDF]
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T. Ito, T. Ueno, M. R. Clarkson, X. Yuan, M. M. Jurewicz, H. Yagita, M. Azuma, A. H. Sharpe, H. Auchincloss Jr, M. H. Sayegh, et al. Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo J. Immunol., June 1, 2005; 174(11): 6648 - 6656. [Abstract] [Full Text] [PDF]
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T. Shin, K. Yoshimura, T. Shin, E. B. Crafton, H. Tsuchiya, F. Housseau, H. Koseki, R. D. Schulick, L. Chen, and D. M. Pardoll In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses J. Exp. Med., May 16, 2005; 201(10): 1531 - 1541. [Abstract] [Full Text] [PDF]
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S. E. Sandner, M. R. Clarkson, A. D. Salama, A. Sanchez-Fueyo, C. Domenig, A. Habicht, N. Najafian, H. Yagita, M. Azuma, L. A. Turka, et al. Role of the Programmed Death-1 Pathway in Regulation of Alloimmune Responses In Vivo J. Immunol., March 15, 2005; 174(6): 3408 - 3415. [Abstract] [Full Text] [PDF]
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A. Saudemont, N. Jouy, D. Hetuin, and B. Quesnel NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells Blood, March 15, 2005; 105(6): 2428 - 2435. [Abstract] [Full Text] [PDF]
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Y. Iwai, S. Terawaki, and T. Honjo PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells Int. Immunol., February 1, 2005; 17(2): 133 - 144. [Abstract] [Full Text] [PDF]
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T. Ito, C. Nishiyama, M. Nishiyama, H. Matsuda, K. Maeda, Y. Akizawa, R. Tsuboi, K. Okumura, and H. Ogawa Mast Cells Acquire Monocyte-Specific Gene Expression and Monocyte-Like Morphology by Overproduction of PU.1 J. Immunol., January 1, 2005; 174(1): 376 - 383. [Abstract] [Full Text] [PDF]
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Y.-F. He, G.-M. Zhang, X.-H. Wang, H. Zhang, Y. Yuan, D. Li, and Z.-H. Feng Blocking Programmed Death-1 Ligand-PD-1 Interactions by Local Gene Therapy Results in Enhancement of Antitumor Effect of Secondary Lymphoid Tissue Chemokine J. Immunol., October 15, 2004; 173(8): 4919 - 4928. [Abstract] [Full Text] [PDF]
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A. Saudemont and B. Quesnel In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis Blood, October 1, 2004; 104(7): 2124 - 2133. [Abstract] [Full Text] [PDF]
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X. Zhong, C. Bai, W. Gao, T. B. Strom, and T. L. Rothstein Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger Int. Immunol., August 1, 2004; 16(8): 1181 - 1188. [Abstract] [Full Text] [PDF]
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Y. E. Latchman, S. C. Liang, Y. Wu, T. Chernova, R. A. Sobel, M. Klemm, V. K. Kuchroo, G. J. Freeman, and A. H. Sharpe PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells PNAS, July 20, 2004; 101(29): 10691 - 10696. [Abstract] [Full Text] [PDF]
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S. Radhakrishnan, L. T. Nguyen, B. Ciric, D. Flies, V. P. V. Keulen, K. Tamada, L. Chen, M. Rodriguez, and L. R. Pease Immunotherapeutic Potential of B7-DC (PD-L2) Cross-Linking Antibody In Conferring Antitumor Immunity Cancer Res., July 15, 2004; 64(14): 4965 - 4972. [Abstract] [Full Text] [PDF]
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P. Smith, C. M. Walsh, N. E. Mangan, R. E. Fallon, J. R. Sayers, A. N. J. McKenzie, and P. G. Fallon Schistosoma mansoni Worms Induce Anergy of T Cells via Selective Up-Regulation of Programmed Death Ligand 1 on Macrophages J. Immunol., July 15, 2004; 173(2): 1240 - 1248. [Abstract] [Full Text] [PDF]
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M. Y. Balkhi, V. K. Latchumanan, B. Singh, P. Sharma, and K. Natarajan Cross-regulation of CD86 by CD80 differentially regulates T helper responses from Mycobacterium tuberculosis secretory antigen-activated dendritic cell subsets J. Leukoc. Biol., May 1, 2004; 75(5): 874 - 883. [Abstract] [Full Text] [PDF]
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M. A. Holsti, T. Chitnis, R. J. Panzo, R. T. Bronson, H. Yagita, M. H. Sayegh, and A. O. Tzianabos Regulation of Postsurgical Fibrosis by the Programmed Death-1 Inhibitory Pathway J. Immunol., May 1, 2004; 172(9): 5774 - 5781. [Abstract] [Full Text] [PDF]
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K. Matsumoto, H. Inoue, T. Nakano, M. Tsuda, Y. Yoshiura, S. Fukuyama, F. Tsushima, T. Hoshino, H. Aizawa, H. Akiba, et al. B7-DC Regulates Asthmatic Response by an IFN-{gamma}-Dependent Mechanism J. Immunol., February 15, 2004; 172(4): 2530 - 2541. [Abstract] [Full Text] [PDF]
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C. Blank, I. Brown, A. C. Peterson, M. Spiotto, Y. Iwai, T. Honjo, and T. F. Gajewski PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells Cancer Res., February 1, 2004; 64(3): 1140 - 1145. [Abstract] [Full Text] [PDF]
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I. Lee, L. Wang, A. D. Wells, Q. Ye, R. Han, M. E. Dorf, W. A. Kuziel, B. J. Rollins, L. Chen, and W. W. Hancock Blocking the Monocyte Chemoattractant Protein-1/CCR2 Chemokine Pathway Induces Permanent Survival of Islet Allografts through a Programmed Death-1 Ligand-1-Dependent Mechanism J. Immunol., December 15, 2003; 171(12): 6929 - 6935. [Abstract] [Full Text] [PDF]
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T. Kanai, T. Totsuka, K. Uraushihara, S. Makita, T. Nakamura, K. Koganei, T. Fukushima, H. Akiba, H. Yagita, K. Okumura, et al. Blockade of B7-H1 Suppresses the Development of Chronic Intestinal Inflammation J. Immunol., October 15, 2003; 171(8): 4156 - 4163. [Abstract] [Full Text] [PDF]
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T. Shin, G. Kennedy, K. Gorski, H. Tsuchiya, H. Koseki, M. Azuma, H. Yagita, L. Chen, J. Powell, D. Pardoll, et al. Cooperative B7-1/2 (CD80/CD86) and B7-DC Costimulation of CD4+ T Cells Independent of the PD-1 Receptor J. Exp. Med., July 7, 2003; 198(1): 31 - 38. [Abstract] [Full Text] [PDF]
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Y. Iwai, S. Terawaki, M. Ikegawa, T. Okazaki, and T. Honjo PD-1 Inhibits Antiviral Immunity at the Effector Phase in the Liver J. Exp. Med., July 7, 2003; 198(1): 39 - 50. [Abstract] [Full Text] [PDF]
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M. J. I. Ansari, A. D. Salama, T. Chitnis, R. N. Smith, H. Yagita, H. Akiba, T. Yamazaki, M. Azuma, H. Iwai, S. J. Khoury, et al. The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice J. Exp. Med., July 7, 2003; 198(1): 63 - 69. [Abstract] [Full Text] [PDF]
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A. D. Salama, T. Chitnis, J. Imitola, M. J. I. Ansari, H. Akiba, F. Tushima, M. Azuma, H. Yagita, M. H. Sayegh, and S. J. Khoury Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis J. Exp. Med., July 7, 2003; 198(1): 71 - 78. [Abstract] [Full Text] [PDF]
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P'n. Loke and J. P. Allison PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells PNAS, April 29, 2003; 100(9): 5336 - 5341. [Abstract] [Full Text] [PDF]
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