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B-Mediated Transcription of CD86 Gene in APC1
Departments of
*
Pathology and
Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and
Department of Surgery, Universita Degli Studi di Roma "La Sapienza," Instituto di II Clinica Chirurgica Servizio Trapianti d’Organo, Rome, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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B binding site, at -612 of the CD86
promoter, is essential for Th-induced transcription. In cultures
containing Th and Ts, Ts inhibit Th-induced NF-B activation in APC.
Together, these findings indicate that Ts inhibition of NF-B
activation in APC is a means by which they regulate the activation and
proliferation of Th. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Human Ts derive from an oligoclonal population of CD8+CD28- T cells which recognize specific MHC-class I/Ag complexes on the surface of APC (10, 11, 12). Allospecific, xenospecific, and nominal Ag-specific suppressor T cell lines (TCL) can be generated in vitro by successive rounds of stimulating human T cells with allogeneic, xenogeneic, or Ag-pulsed autologous APC. CD8+CD28- Ts from these TCL inhibit proliferation of CD4+ Th with cognate-Ag specificity. Ts activation via TCR interaction with class I MHC/Ag complexes requires cell-to-cell interaction between Ts and the APC used for Th priming (10, 11). In this system, APC act as a temporal bridge between Ts, which recognize MHC-class I/peptide complexes, and Th, which recognize MHC-class II complexes. Ts render the APC unable to up-regulate B7 molecules or to provide efficient costimulation of Th. The level at which the expression of B7 molecules by APC is regulated by Ts is currently unknown.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Alloreactive TCL were generated as previously described (10, 11, 12, 13). Briefly, PBMC were separated from buffy coats by Ficoll-Hypague centrifugation. Responding PBMC (1 x 106/ml) were stimulated in 24-well plates with irradiated APC (3000 rad; 0.5 x 106/ml) obtained from allogeneic PBMC by depletion of CD2+ cells. Cells were cocultured for 7 days in complete medium (RPMI 1640 supplemented with 10% human serum, 2 mM L-glutamine, and 50 µg/ml gentamicin; Life Technologies, Grand Island, NY). After 7 days, responding cells were collected, washed, and rechallenged with the original stimulating cells. After 3 days, rIL-2 (Boehringer Mannheim, Indianapolis, IN) was added (10 U/ml) and the cultures were expanded for an additional 4 days. Th and Ts cells were then harvested from the TCL. CD4+ Th cells were obtained by depleting CD8+, CD14+, and CD19+ cells from the TCL. CD8+CD28- Ts cells were obtained by depleting CD4+, CD14+, CD19+, and CD28+ cells, as previously described (10).
Expression of CD86 on human B cells
The expression of CD86 on human B cells was analyzed by ELISA. Lysates prepared from purified human B cells were adhered to 96-well trays at 4°C for 24 h. CD86 Ag was detected using a mouse anti-human CD86 mAb (PharMingen, San Diego, CA).
Cell cultures
Th cells (3 x 106) were incubated with CD2-depleted PBMC (3 x 106) from the stimulating cell donor in the presence or absence of Ts cells (1.5 x 106). After 6 or 48 h of incubation (as indicated), CD19+ B cells were isolated from the cultures using CD19-coupled Dynal beads (Great Neck, NY).
Northern blot analysis
Acid phenol-guanidinium thiocyanate procedure (Trizo, Molecular
Research Center, Cincinnati, OH) was used to isolate total RNA from the
human B cells. The concentration of total RNA was determined by
absorption at OD260/280. Total RNA (20
µg/lane) was subjected to electrophoresis. After separation on a
formaldehyde gel (0.7%), RNA was transferred to a Gene Screen
hybridization filter (NEN, Boston, MA) and cross-linked by a UV
cross-linker (Stratagene, La Jolla, CA). The filter was then hybridized
with the full-length human CD86 cDNA probe labeled with
[
-32P]dCTP using the Random Primer Labeling
System (Strategene). After washing twice at room temperature (15
min/wash) with 2x SSC containing SDS (0.1%) and once for 30 min at
60°C with 0.1x SSC containing SDS (0.1%), the filter was subjected
to autoradiography overnight at -80°C. G3PDH mRNA was detected using
G3PDH cDNA (Clontech Laboratories, Palo Alto, CA) to normalize samples
for mRNA content.
Nuclear run-on transcription assay
Nuclear run-on transcription assays were performed as previously
described (14). Human B cells, isolated as described
above, were washed twice with cold PBS, pelleted, and resuspended in 10
ml of lysis buffer containing 0.01 M Tris (pH 7.4), 10 mM NaCl, 1 mM
DTT, 0.5% (v/v) Nonidet P-40, 0.5 mM PMSF, and 100 µg/ml aprotinin.
After 15 min of incubation on ice, the lysate was homogenized and then
centrifuged at 500 x g for 5 min at 4°C. The nuclear
pellet was washed once with 4 ml of lysis buffer and centrifuged at
500 x g for 5 min at 4°C. The supernatant was
discarded and the nuclei were resuspended in 0.2 ml reaction buffer
containing 10 mM Tris (pH 8.0), 5 mM MgCl2, 300
mM KCl, 1 mM DTT, 0.5 mM ATP, 0.5 mM cytidine 5'-triphosphate, 0.5 mM
GTP, and 200 µCi of [-32P]UTP (3000 Ci/mM;
Amersham, Arlington, Heights, IL). After 1 h of incubation at
30°C, RNA was extracted and resuspended in hybridization buffer
containing 50 mM PIPES (pH 6.8), 10 mM EDTA, 600 mM NaCl, 0.2% SDS,
and 100 µg/ml denatured salmon sperm DNA. After prehybridization at
80°C for 2 h in hybridization buffer containing 0.1% SDS, RNA
was hybridized to denatured human CD86 cDNA and ß-actin cDNA, and
slot-blotted on nylon filters at 42°C for 72 h. After
hybridization, filters were washed three times for 1 h in 2x SSC
containing 0.1% SDS, then briefly air-dried and exposed to x-ray film
for 4 days. Human CD86 cDNA and ß-actin cDNA, denatured by incubation
with 0.3 M NaOH for 30 min at 65°C, were spotted onto nylon filters
and cross-linked with a UV cross-linker (Fisher, Pittsburgh,
PA).
Isolation of a human CD86 genomic clone
A 1.4-kb genomic DNA clone, including the 5'-flanking fragment
and part of the first exon of human CD86 gene, was isolated by
screening a 
DH3 library (Stratagene) with a synthetic
oligonucleotide probe that represents 120 nucleotides of the first exon
of CD86 (15). The 1.4-kb insert was subcloned into
pCR-Script vector (Stratagene) and sequenced in both directions. The
1.4-kb clone contained 77 nucleotides of the first exon and 1245 bp
upstream of the transcription site of the CD86 gene.
Generation of 5'-deleted CD86 promoter constructs
CD86 promoter-reporter constructs representing either 5'-deleted
CD86 upstream sequences or site-directed mutants of the -612 NF-B
or -238 NF-B binding sites were generated by PCR then by subcloning
into the pGL3-Basic vector (Promega, Madison, WI). In these PCRs, the
CD86 genomic clone (described above) was used as a template. For
5'-deletion mutants, oligonucleotides used for priming were synthesized
based on the sequence of the 5'-flanking region of human CD86 gene. In
these reactions, the priming oligonucleotides represented overlapping
sense and antisense sequences that amplified the entire pGL3 plasmid
and insert. The 5'-deletion constructs represent -1179 to +48 (1.2
kb), -781 to +48 (0.8 kb), -407 to +48 (0.4 kb), and -212 to +48
(0.2 kb) of the CD86 gene. For the NF-B binding site mutants, DNA
primers were synthesized that contained the mutated NF-B binding
site sequences at -612 and -238. The constructs containing these
mutated NF-B binding sites represent nucleotides -1179 to +48 of
the CD86 gene. DNA sequencing on both strands of the inserts confirmed
the sequence of all constructs employed for transfection assays.
CD86 reporter assays
Transfected B cells were cultured for 48 h in the presence of Th, Ts, mixtures of Th and Ts, or medium alone. B cell transfection was performed with DMRIE-C reagent (Life Technologies) according to the manufacturer’s recommendations. Briefly, 1 x 106 cells were cotransfected using 4 µg of CD86 promoter-GL3 reporter plasmid, and 1 µg of pSV ß-galactosidase, which served as an internal control to normalize transfection efficiency, in 8 µl of DMRIE-C reagent. Twenty-four hours after transfection, Th, Ts, mixtures of Th and Ts cells at the indicated ratio, or control medium was added to B cell cultures. After an additional 24 h, cells were harvested, lysed, and assayed for luciferase activity by a luminometer (Promega). Statistical analysis of at least three separate experiments were performed using ANOVA.
EMSA
Oligonucleotide probes corresponding to the -612 NF-B
binding site sequence of human CD86 promoter were generated by
annealing the synthetic oligonucleotides 5'-CTTAGGGACATCTATTAA-3' and
5'-TTAATAGATGTCCCTAAG-3'. The probe (250 pg), end labeled with
[
-32P]ATP, was incubated with 8 µg of B
cell nuclear extract(s) at room temperature for 30 min. For competition
assays, the nuclear extract was first incubated with 100-fold excess of
unlabeled double-stranded oligonucleotides representing the -612
NF-B site, NF-B consensus site (5'-AGTTGAGGGGACTTTCCCAGGC-3'), or
SP1 consensus site (5'-ATTCGATCGGGGCGGGGCGAGC-3') for 15 min at room
temperature and then incubated with the end-labeled -612 NF-B probe
for 30 min under the same conditions. For supershift assays, nuclear
extracts were incubated with Abs to p50 or p65 (Santa Cruz
Biotechnology, Santa Cruz, CA) for 4 h at 4°C before the
addition of the labeled -612 NF-B probe. Samples were separated in
8% polyacrylamide gels and the gels were subjected to autoradiography
overnight at -80°C.
Western blotting assays
Ten micrograms of nuclear extracts from B cells, purified from 3- or 6-h cultures with Th, Ts, mixtures of Th and Ts, or medium, were separated in 12% polyacryloamide gels and transferred to nitrocellulose membranes. Membranes were briefly soaked in ddH2O, then blocked in Tris-buffered saline (Bio-Rad Laboratories, Hercules CA)/0.05% Tween 20 (TTBS) containing 5% BSA for 1 h at room temperature. Membranes were probed with either anti-p50 or anti-p65 (Santa Cruz Biotechnology) at 1:200 dilution in TTBS for 1 h, washed four times with TTBS, and then incubated with goat anti-rabbit IgG conjugated to alkaline phosphatase (Amersham) at 1:10,000 dilution in TTBS containing 5% goat serum. Membranes were washed four times with TTBS and developed using enhanced Hyperfilm-ECL (Amersham). Antiactin Ab (Santa Cruz Biotechnology) was used as control.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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A). However, Ts
inhibit the Th-induced increase in B cell CD86 protein in a
dose-dependent manner (Fig. 1B).
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C).
B cells cultured with Ts cells alone showed no significant change in
CD86 mRNA (Fig. 1C). However, Ts inhibited the Th-induced
up-regulation of B cell steady-state CD86 mRNA levels in a
dose-dependent manner (Fig. 1D).
To determine whether the Ts effect on CD86 expression occurs at the
level of transcription, we performed nuclear run-on assays
(14) on B cells purified from cultures containing Th, Ts,
Th/Ts mixtures, or medium alone. Th induced a 3.7-fold increase in B
cell CD86 transcription compared with that in control B cells (Fig. 1E). Ts cells did not alter B cell CD86 transcription.
However, Ts inhibited the Th-induced increase in B cell CD86
transcription. These data indicate that Ts suppress the Th-induced
up-regulation of B cell CD86 expression at the level of
transcription.
To further characterize the mechanism by which CD86 transcription in B
cells is regulated by Th and Ts, we cloned a 1.4-kb genomic fragment
that contains 1245 bp of the 5'-flanking region upstream of the human
CD86 gene (15) (Fig. 2A). We searched for known
transcription-factor binding-consensus sequences in the 5'-flanking
sequence using the Transfast program (Gesellschaft für
Biotechnologische, Braunschweig, Germany). This search revealed
multiple potential transcription-factor binding sequences, including at
least two canonical NF-B binding sites, one at -612 and another at
-238 (Fig. 2A).
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B). The resulting constructs (termed pGL.Luc/1179,
pGL.Luc/781, pGL.Luc/407, and pGL.Luc/212) were transfected into B
cells to measure their transcriptional activities. The control
construct contained the 1179-bp DNA element cloned into pGL3-Basic
vector in the opposite orientation (pGL.Luc/1179R). When exposed to Th
cells, B cells transfected with reporters driven by the 1179- and
781-bp DNA elements showed significant increases in luciferase activity
(6.8- and 5.7-fold, respectively) compared with B cells transfected
with the control construct (p < 0.01). In
contrast, Th cells did not induce luciferase activity in B cells
transfected with the 407- and 212-bp DNA elements. Ts inhibited the
Th-induced luciferase activity in B cells transfected with the 1179- or
781-bp DNA elements (p < 0.01) (Fig. 2B). Hence, Th cells trigger transcription driven by the
1179- and 781-bp elements in B cells, and Ts inhibit this effect. In
addition, these data indicate that Th and Ts control CD86 transcription
by exerting effects on a segment of the 5'-flanking DNA located between
-1179 and -407 upstream of the transcription start site of CD86.
Because the transcription factor NF-B is known to play an important
role in many of the biological effects exerted by CD40, we focused on
the NF-B binding site at -612 (17).
To determine whether the -612 binding site is functionally important
in the B cell CD86 response to Th and Ts signals, we generated a
reporter construct driven by the 1179-bp DNA segment that contained a
mutated -612 NF-B binding site (Fig. 2C). As controls,
reporter constructs that contained either a mutated NF-B consensus
binding site at -238 or the mutated NF-B binding sites at -612 and
-238 were used. In the absence of Th, B cells transfected with the
-612-mutated 1179-bp construct (pGL.Luc/-612 mut) showed levels of
background luciferase activity similar to those of B cells transfected
with the wild-type 1179-bp construct (pGL.Luc/1179). In the presence of
Th, B cells transfected with the wild-type construct or the mutated
-238 NF-B consensus binding site (pGL.Luc/-238 mut) showed
enhanced luciferase activity (6.7- and 5.8-fold, respectively), whereas
Th-activated B cells transfected with the -612-mutated construct
showed substantially less activity (78% less than the wild-type
construct) (p < 0.01) (Fig. 2C).
The data suggest that the -612 NF-B consensus binding site within
the CD86 promoter plays an important role in the transcriptional
activation of CD86 expression induced by T helper cells in B cells.
To determine whether the -612 NF-B consensus site also plays a role
in CD40 triggering of CD86 transcription in APC (18), the
following experiments were performed. CD2-depleted PBMC were
transfected with the 1179-bp wild-type (pGL.Luc/1179) and -612 mutant
(pGL.Luc/-612 mut) reporter constructs and incubated with 293 cells
expressing CD40L (CD40L+ 293 cells) or with
control CD40L- 293 cells (19).
After 48 h, CD19+ B cells and
CD14+ monocytes were isolated from the cultures
and luciferase activity was measured. CD40 triggering of B cells
resulted in a 7.6-fold increase in activity driven by the wild-type
promoter element and only a 2.3-fold increase in activity driven by the
-612 mutant reporter (Fig. 3).
Similarly, CD40 triggering of monocytes induced a 7.8-fold increase,
whereas the -612 mutant induced only a 2.2-fold increase of luciferase
activity (Fig. 3). These data show that CD86 transcription induced by
CD40 ligation in APC depends on the -612 NF-B consensus
site.
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B binding site and the transcription factors which bind to it,
EMSAs were performed on nuclear extracts from B cells purified from
cultures containing Th, Ts, Th/Ts mixtures, or medium. For these
studies, a synthetic 18-mer probe derived from the -612
NF-B-consensus binding-site sequence in the CD86 promoter was used.
Th induced a 6.9-fold increase in the intensity of a band corresponding
to retardation of the -612 NF-B probe (Fig. 4A) over the level seen in B
cells cultured without Th. Ts inhibited the Th-induced effect in a
dose-dependent manner (Fig. 4B). Control experiments using
unlabeled, double-stranded oligonucleotides confirmed the specificity
of the -612 NF-B probe because the signal was inhibited by
preincubation with either unlabeled -612 NF-B or consensus NF-B
oligonucleotides, but not by preincubation with an Sp-1
oligonucleotides (Fig. 4C). These data suggest that
the -612 NF-B probe binds specifically to activated NF-B.
Kinetic analysis of NF-B induction showed activation at 3 h,
maximal activation at 6 h, and a return to baseline at 12 h
(Fig. 4D).
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B binding site, we performed supershift experiments using
Abs specific for p65 and p50. The 32P-labeled
-612 NF-B probe was added to nuclear extracts isolated from B cells
that had been preactivated by Th cells and preincubated with Abs as
indicated above. The anti-p65 and anti-p50 Abs retarded the
mobility of the -612 NF-B probe/protein complex (Fig. 4E). Kinetic studies using Western blotting showed that Th
increased the levels of nuclear p65 and p50, and that Ts inhibited this
effect (Fig. 4F). These data indicate that the -612 NF-B
probe binds specifically to NF-B and most likely interacts with
p65/p50 heterodimers. Hence, cell-to-cell interactions between Th and
APC induce APC to activate NF-B, which plays an important role in
driving the transcription of CD86.
Similar to the role that NF-B plays in CD86 transcription, NF-B
activation previously has been shown to drive the transcription of
CD80, the other B7 molecule (20). Both of these molecules,
CD80 and CD86, are up-regulated following ligation of CD40, which has
been shown to induce NF-B activation (21, 22, 23).
Taken together with our previous finding that Ts cells inhibit CD40
signaling in APC, the present study indicates that Ts modulate Th
reactivity in vitro by regulating NF-B activation in APC. This
finding may have importance for the development of new immunomodulatory
strategies for the treatment of autoimmune diseases and transplant
rejection.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nicole Suciu-Foca, Department of Pathology, P&S 14-403, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. E-mail address:
3 Abbreviations used in this paper: Ts, T suppressor cells; TCL, T cell lines.
Received for publication June 9, 1999. Accepted for publication September 22, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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B. J. Immunol. 153:4357.[Abstract]
B. J. Exp. Med. 183:777. B. J. Immunol. 153:4357.
B, AP-1 and NF-AT during B cell stimulation through the CD40 receptor. Int. Immunol. 7:151.B components in primary B cells. Int. Immunol. 10:285.This article has been cited by other articles:
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