* Experimental Immunology Branch, Division of Basic Sciences, and
Transplantation Therapy Section, Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892;
Transgenic Mouse Model, Science Application International Corporation, National Cancer Institute Frederick Cancer Research and Development Center, Frederick, Maryland 21702; and
Institute of Human Virology, University of Maryland, Baltimore, Maryland 21201
Correspondence: Dr. Ronald E. Gress, National Cancer Institute, Experimental Immunology Branch, Bldg. 10, Rm. 4B14, 10 Center Dr., Bethesda, MD 20892-1360. E-mail: gressr{at}dc10a.nci.nih.gov
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and failed to express the macrophage
inflammatory protein (MIP)-1
and MIP-1ß genes. Splenic T cells
from ICER-transgenic mice showed a defect in proliferation and lacked a
mixed lymphocyte reaction response, implying that ICER-mediated
inhibition of cytokine and chemokine expression might play an important
role in T-cell inactivation.
Key Words: transcription factors • cytokines • chemokines
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Here we demonstrate that on cAMP-mediated induction, ICER proteins
reached high levels in T cells and effectively competed with and
thereby repressed transcription mediated by bZIP proteins (e.g., by the
ubiquitously expressed activator CREB). Such competition for CREB is
presumably highly efficient in T cells because they do not express
activator forms of CREM [7
], which are constitutively
expressed in a stage-specific fashion in tissues of the
hypothalamo-pituitary-gonadal axis [8
]. ICER does not
possess a transactivation domain, an element required for the
recruitment of CREB-binding protein (CBP). Therefore, the binding of
ICER to the CRE might lead to the uncoupling of CBP or its homologue,
p300 (CBP/p300), abrogating early stages of transcriptional initiation
because of the lack of CBP/p300-associated histone acetyltransferase
activity. This results in a failure to maintain the transcriptionally
competent conformation of chromatin [9
]. Furthermore, in
the absence of a CBP-p300 complex, interactions of the nuclear factor
of activated T cells (NFAT) and nuclear factor 
B are likely to be
affected because their full transcriptional activity is dependent on
interaction with CBP-p300 [10
, 11
].
Therefore, it is possible that ICER’s competition with bZIP proteins
(e.g., CREB), bound to CRE-like motifs positioned adjacent to NFAT or
nuclear factor-B binding sites in the context of cytokine and
chemokine promoters, uncouples CBP-p300 and thereby aborts crosstalk
between Rel- and bZIP-mediated transcription [12
].
It is well established that T helper (Th) cells do not compose a
homogeneous population but rather are subdivided, on the basis of
cytokine expression, into at least two subsets, Th 1 and Th 2 (for a
review, see ref. 13
). Th 1 cells secrete predominantly interleukin
(IL)-2 and interferon (IFN)-, whereas Th 2 cells produce IL-4, IL-5,
IL-9, IL-10, and IL-13. There is good evidence that the ratio of the
abundance of Th 1 and Th 2 cells is relevant to the biology of a wide
variety of syndromes, including autoimmune diseases, allergic
conditions, and infectious diseases (for a review, see ref. 14
). Over
the past 10 years, the ability of numerous chemokines to attract
different types of blood leukocytes to sites of infection and
inflammation has been demonstrated [15
]. The
differential expression of chemokines and their receptors might
dictate, to a large extent, the migration and tissue homing of Th 1 and
Th 2 cells [16
, 17
]. The expression of
chemokine receptors could also result in different susceptibilities of
Th 1 and Th 2 cells to different strains of HIV using different fusion
coreceptors [18
]. Therefore, chemokines are part of an
effector and amplification mechanism relevant to polarized Th 1- and Th
2-mediated immune responses.
Here we demonstrate that cAMP-mediated inhibition of endogenously
expressed cytokines, a characteristic of Th 1 and Th 2 phenotypes,
correlated with the induction of ICER in both subsets of cells. It is
important that Th-specific expression of certain chemokines
[represented by macrophage inflammatory proteins (MIP-1) and
MIP-1ß] is also susceptible to ICER-mediated transcriptional
attenuation. To examine the direct role of ICER in cAMP-mediated
inhibition of cytokine and chemokine gene expression, we generated
transgenic mice expressing ICER under the control of the
lymphocyte-specific proximal lck promoter. On stimulation,
transgenic thymocytes overexpressing ICER exhibited reduced levels of
IL-2 and IFN- and failed to express MIP-1 and MIP-1ß. Moreover,
splenic T cells from ICER-transgenic mice showed a defect in
proliferation and lacked a mixed lymphocyte reaction response,
suggesting that ICER-mediated transcriptional attenuation of cytokine
and chemokine gene expression may compromise the T-cell response.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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75% CD4+ cells
and 20% CD8+ cells (data not shown). After
paramagnetic-bead separation for T cells, <1% CD56+
CD16+ [natural killer (NK) cells], CD3+
CD56+ double-positive NK T cells expressing both T and NK
cell markers, CD19+ B lymphocytes, and CD14+
monocytes were detected (data not shown).
Stable polarization of human PBL T cells toward Th 1 or Th 2
phenotypes after polyclonal activation
Polarization was done by the method of Asselin et al.
[20
]. Polarized IL-12-derived Th 1-like or IL-4-derived
Th 2-like human PBL T cells were restimulated with either
phytohemagglutinin (PHA; Gibco-BRL, Rockville, MD) or phorbol myristate
acetate (PMA; 10 ng/mL) plus ionomycin (1 µg/mL) for 6 h in the
absence or presence of forskolin (0.1 mM final concentration). T
lymphocytes (containing >95% CD3+ cells) were typically
obtained after in vitro priming and polarization toward the Th 1- or Th
2-dominant phenotype. The non-CD3+ cells were
CD14+ (1% in Th 1 and <1% in Th 2), CD19+
(1% in Th 1 and 2% in Th 2), and CD16+ (1% in Th 1 and
5% in Th 2). In the experiments detailed here, the cells were cultured
for a total of 2 weeks prior to restimulation, and Th 1- and Th 2-like
populations shifted significantly toward the memory phenotype,
represented by the CD45RO marker (91% of CD45RO+ cells for
Th 1-like phenotype and 78% of CD45RO+ cells for Th 2-like
phenotype). Typically, the Th 1-like population contained 55%
CD4+ cells and 35% CD8+ cells. The Th 2-like
population usually contained 60% CD4+ and 15%
CD8+ cells (data not shown).
Flow cytometry
PBLs were analyzed before and after separations on
magnet-activated cell-sorting columns, using FACSort equipment (Becton
Dickinson, Paramus, NJ). Cells were stained at 4°C using
Ca2+- and Mg2+-free phosphate-buffered saline
with 0.5% bovine serum albumin and 0.025% sodium azide as a
diluent/wash fluorescence-activated cell sorting buffer. Nonspecific Fc
receptor binding was blocked by incubation with a 0.2-mg/mL solution of
human immunoglobulin G (Sigma Chemical Co., St. Louis, MO) for 10–15
min; then cells were triple stained with fluorescein isothiocyanate-,
phycoerythrin (PharMingen, San Diego, CA)-, and Tri-Color (Caltag,
Burlingame, CA)-conjugated antibody for 30 min. After being washed with
the cold fluorescence-activated cell sorting buffer, cells were fixed
in 1% paraformaldehyde in phosphate-buffered saline. Three-color
analyses were then performed.
Immunoprecipitation
Cells were metabolically labeled with 35S Translabel
(ICN Biomedicals, Costa Mesa, CA) according to established protocols
and lysed in radioimmunoprecipitation assay buffer [0.15 M NaCl, 50 mM
Tris-Cl (pH 7.2), 1% Triton X-100, 1% sodium deoxycholate, 0.1%
sodium dodecyl sulfate]. The lysate was supplemented with Complete
protease inhibitor cocktail (Boehringer Mannheim, Mannheim, Germany),
clarified by centrifugation at 20,800 x g and 4°C
for 30 min, and precleared using protein A-Sepharose 4B beads
(Pharmacia, Uppsala, Sweden). Immune complexes were collected onto
protein A-Sepharose 4B beads that were prebound with CS4 CREM-specific
antiserum, rocked for 30 min at 4°C, and washed three times with
radioimmunoprecipitation assay buffer. Immune complexes were eluted
from beads with Laemmli sample buffer and resolved by sodium dodecyl
sulfate–15% polyacrylamide gel electrophoresis under reducing
conditions. The 35S signal was enhanced by treatment of the
gel with 2,5-diphenyloxazole (Sigma Chemical). 35S-labeled
proteins were detected by exposure of O-XAR film (Eastman Kodak,
Rochester, NY) for 1–10 days at -70°C.
RNase protection assay
RNA extraction was performed using an RNeasy kit (Qiagen,
Valencia, CA). The RNA probe for ICER, generated from pJL5 by either
XhoI or XbaI digestion, corresponds to the
full-length cDNA of human ICERII (described previously
[7
]). RNA probes hAPO3 and mAPO3 (PharMingen) were
labeled with [-32P]UTP using reagents from an RNA
probe kit (Ambion, Austin, TX). These probes were used for RNase
protection studies performed according to the protocol provided by
Ambion (RPAII ribonuclease protection assay kit).
Production and characterization of ICER-transgenic mice
A 0.36-kb fragment encompassing the ICER coding sequence, driven
by the proximal lck promoter, was introduced into a mouse
germ line by pronuclear microinjection [21
]. Of the
several independent founder lines generated, three were selected for
analysis on the basis of their levels of expression of the transgene.
These lines proved to be unstable over time. A different construct was
used to derive another set of founder lines which is not included in
this report. For measurements of lymphocyte proliferation, freshly
isolated lymphocytes (2 x 105) were cultured in
triplicate in 200 µL of Dulbecco’s modified Eagle medium
supplemented with 10% fetal calf serum (Gibco-BRL), using 96-well
tissue culture plates (Becton Dickenson Labware, Franklin Lakes, NJ).
Lymphocytes were activated for 48 h at 37°C by treatment with
PMA (10 ng/mL) and ionomycin (1 µg/mL), the anti-CD3 monoclonal
antibody 145.2C11 (10 µg/mL, immobilized on plastic tissue culture
plates), or concanavalin A (Con A; 2 µg/mL). Forty-eight hours after
activation, cells were labeled for 18 h by incubation in
[3H]thymidine-containing tissue culture medium (1
µCi/mL; specific activity, 2 Ci/mmol) (Amersham, Little Chalfont,
UK). Cells were collected onto glass fiber filter mats, and
[3H]thymidine incorporation was measured in a
scintillation counter. For measurement of allostimulation, splenocytes
from ICER-transgenic or nontransgenic mice were cocultivated with
either syngeneic splenocytes from CB57BL/6 mice or allogeneic
splenocytes from BALB/c mice for 48 h, after which
[3H]thymidine labeling was performed, and radioactivity
was determined as described above.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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, ICERI and ICERII (denoted as
ICER in Fig. 1
), were detected [4
]. Accumulation of
ICER protein after forskolin or PGE2 treatment reached a
plateau 12 h (F12, P12) or 18 h (F18, P18) later (Fig. 1 ,
lanes 5 and 13). Our findings indicate that significant amounts of ICER
protein can be readily induced in mature human PBL T cells in response
to physiologically relevant ligands such as PGE2
[25
]. Furthermore, our data suggest that
PGE2 may activate a signal transduction pathway(s) to cause
the accumulation of stable ICER protein in human PBL T cells. These
observations differ substantially from earlier findings, obtained in a
study of developing human medullary thymocytes, in which the induction
of ICER after forskolin treatment was found to occur transiently, with
a peak seen at 3 h and a complete disappearance of detectable
ICER-specific protein evident by 12 h [22
]. In
contrast, in mature PBL T cells, ICER protein is stably induced for at
least 18 h after forskolin or PGE2 treatment.
Therefore, ICER may play an important role in cAMP-mediated
transcriptional attenuation in human PBL T cells.
 View larger version (89K): [in a new window] |
Figure 1. ICER is readily induced in human PBLs after forskolin (F) (0.1 mM final
concentration) or PGE2 (P) (500 ng/mL final concentration)
treatment. Immunoprecipitation of total 35S-labeled cell
lysates with CREM-specific antiserum (C) and normal rabbit serum (N)
demonstrates accumulation of ICER proteins in T cells (see Materials
and Methods) after 3, 12, and 18 h of forskolin (F3, F12, and F18,
respectively) or PGE2 (P3, P12, and P18, respectively)
treatment. After 3 h of forskolin or PGE2 treatment
(lanes 3 and 9, respectively), distinct signals were detected for both
the comigrating ICER isoforms (ICERI and ICERII, denoted as ICER) and
their comigrating counterparts lacking exon- (ICERI and
ICERII; denoted as ICER) [4
]. ICER and ICER
proteins were barely detectable in untreated (U) T cells (lanes 1 and
2) but were clearly detectable after 3 h of treatment (compare
lanes 3 and 4 and lanes 9 and 10, respectively), reaching robust levels
after 12 h of forskolin treatment (lane 5) or 18 h of
PGE2 treatment (lane 13).
|
, whereas the Th 2-like population
exhibited moderately increased levels of IL-4 and IL-5 (Fig. 2A
, lane
5), characteristic of the Th 2 phenotype. Furthermore, cAMP-mediated
inhibition of endogenously expressed cytokines, characteristic of both
the Th 1 and Th 2 phenotypes, correlated with the forskolin-mediated
induction of ICER in both subsets of T cells (Fig. 2B
and 2D)
. These
observations suggest that ICER may be responsible for the observed
inhibitory effect of the cAMP-mediated attenuation of cytokine
expression. It is interesting that, after PHA restimulation of in
vitro-polarized Th 1- and Th 2-like cells, only the cells with the Th
1-like phenotype expressed MIP-1ß, which was undetectable in the Th
2-like cells under these conditions (Fig. 2C)
. However, expression of
both MIP-1 and MIP-1ß was inhibited by forskolin (Fig. 2C
, lane
2), which correlated with forskolin-mediated induction of ICER (Fig. 2D
, lane 2). Collectively, these data suggested that ICER may play an
important role in inhibition of numerous cytokine and chemokine genes.
 View larger version (43K): [in a new window] |
Figure 2. Forskolin-mediated transcriptional attenuation of cytokine and
chemokine expression in IL-12-derived (IL-12), Th 1-like and
IL-4-derived (IL-4), Th 2-like cells correlates with induction of ICER.
IL-12- and IL-4-derived Th 1- and Th 2-like populations of PBLs were
restimulated with PHA for 6 h (see Materials and Methods) either
in the absence (-) or the presence (+) of 0.1 mM forskolin (F), and
RNAs were scored for human cytokine (A) or chemokine (C) expression in
parallel with ICER (B and D), using an RNase protection assay (Ambion).
For evaluation of human cytokine expression (A), a Riboquant hCK1 probe
set was used, while for evaluation of human chemokine expression (C) we
used a Riboquant hCK5 probe set (PharMingen). Levels of cytokine (IL-4,
IL-5, IL-9, IL-13, and IFN-) or chemokine (MIP-1 and MIP-1ß)
expression in PHA-activated, IL-12-derived Th 1- and IL-4-derived Th
2-like populations after forskolin treatment are inversely related to
the levels of ICER mRNA (B and D). Templates for the analysis of hL32
and human glyceraldehyde-3-phosphate dehydrogenase housekeeping genes
were included to allow assessment of total RNA levels. Note that each
probe migrated more slowly than its protected band; this was due to
flanking sequences in the probe that were not protected by mRNA. Purity
of in vitro polarized T-cell populations with a Th 1- or Th 2-like
phenotype was evaluated by flow cytometry analysis prior to PHA
restimulation (see Materials and Methods).
|
 View larger version (112K): [in a new window] |
Figure 3. Differential susceptibility of cytokine expression to cAMP-mediated
inhibition in IL-12-derived (IL-12), Th 1-like and IL-4-derived (IL-4),
Th 2-like cells after restimulation. Polarized T cells were
restimulated for 6 h either with P+I [PMA, 10 ng/mL; ionomycin, 1
µg/mL (final concentrations)] or with PHA in the absence (-) or
presence (+) of forskolin (0.1 mM). After restimulation, RNAs were
scored in the RNase protection assay for cytokine expression, using a
Riboquant hCK1 human cytokine probe set (PharMingen). Also shown are
the corresponding RNase-protected probes after hybridization with yeast
RNA in the presence (lane 13) or absence (lane 14) of RNase.
|
promoter
reflect differential expression of IFN- in Th 1 versus Th 2
phenotypes of T cells [30
]. However, in humans, a high
level of expression of IFN- occurs after restimulation in both Th
cell subsets, a finding attributable to a uniform hypomethylation of
the IFN- promoter in both subsets (for a review, see ref.
26
). Nevertheless, after PHA-mediated restimulation, Th
2-like cells were more susceptible to cAMP-mediated inhibition of
IFN- expression (Fig. 3 , lane 12) than are Th 1-like cells (Fig. 3
,
lane 6), which retain residual IFN- expression even in the presence
of forskolin. It is possible that the observed differential
susceptibility to cAMP-mediated inhibition is related to signaling via
other Th 1-specific pathways, such as p38 mitogen-activated protein
kinase, which has been reported to be relevant for IFN- expression
in Th 1 but not Th 2 cells [31
].
Defective expression of cytokines and chemokines in ICER-transgenic
mice is accompanied by impaired T-cell proliferation
To determine whether ICER per se is directly responsible for the
observed transcriptional attenuation of cytokine and chemokine
expression, we generated ICER-transgenic mice expressing the human
ICERII isoform. High-level expression of ICER (Fig. 4A
), under the control of the heterologous lck promoter,
allowed us to test the inhibitory role of ICER in the early expression
of cytokines and chemokines in activated thymocytes in the absence of
forskolin. In contrast to thymocytes from nontransgenic littermates,
which expressed normal amounts of IL-2 and IFN- when activated with
P+I, ICER-transgenic thymocytes exhibited significantly decreased
levels of IL-2 and IFN- after activation (Fig. 4B)
. Moreover,
ICER-transgenic mice failed to express MIP-1 and MIP-1ß as well as
lymphotactin and IFN--inducible protein-10, whereas background
expression of the protein known as RANTES (for regulated on activation,
normal T expressed and secreted), although modest, was almost
unaffected, suggesting a high specificity of ICER-mediated inhibition
(Fig. 4C) .
 View larger version (32K): [in a new window] |
Figure 4. ICER-mediated transcriptional attenuation of expression of cytokines
and chemokines in ICER-transgenic mice. (A) Freshly isolated thymocytes
from ICER-transgenic (lane pairs A and B) or control (lane pairs C and
D) nontransgenic littermates were obtained, and total
35S-labeled cell lysates were assayed by
immunoprecipitation, using a CREM-specific antiserum (single-lanes c)
along with normal rabbit serum (single-lanes n). ICER-transgenic (+) or
control nontransgenic (-) thymocytes were activated with PMA plus
ionomycin for 3 h. RNAs were isolated and analyzed in the RNase
protection assay for cytokine (B) and chemokine (C) production in
parallel using the Riboquant mCK1 and mCK5 probe sets (PharMingen),
respectively. Expression of both IL-2 and IFN- was significantly
reduced, along with expression of MIP-1, MIP-1ß, lymphotactin, and
IFN--inducible protein-10.
|
/ß, and there were normal
numbers of double-negative (CD4- CD8-),
double-positive (CD4+ CD8+), and
single-positive (CD4+ or CD8+) thymocytes and
splenic T cells in transgenic animals (data not shown). Thus, ICER
overexpression did not noticeably disrupt T-cell development. In
contrast, after activation by either Con A, immobilized anti-CD3
monoclonal antibody 2C11, or P+I (Fig. 5B)
, ICER-transgenic splenocytes
displayed proliferative defects of various extents. The most pronounced
differences between ICER-transgenic and wild-type lymphocytes were seen
after mitogenic stimulation with Con A. Treatment with P+I or with
antibody 2C11 resulted in less-pronounced differences in the
proliferation of splenocytes from ICER-transgenic mice (Fig. 5B)
. These
data indicate that the outcome of ICER-mediated inhibition is dependent
on stimulation. Moreover, allogeneic stimulation using splenocytes from
ICER-transgenic or nontransgenic mice, cocultivated with either
syngeneic splenocytes from CB57BL/6 (B6) mice or allogeneic splenocytes
from BALB/c mice in a mixed lymphocyte reaction, yielded markedly
different thymidine uptake levels (Fig. 5C)
. Thus, ICER-transgenic
splenocytes are clearly functionally distinct from their nontransgenic
counterparts.
 View larger version (28K): [in a new window] |
Figure 5. A proliferative defect in lymphocytes from ICER-transgenic mice. (A)
Cell yields from the thymus and spleen of transgenic and nontransgenic
animals. (B) Proliferation of splenocytes activated for 48 h with
Con A, PMA plus ionomycin (PMA + Ionophore), or immobilized
anti-CD3 monoclonal antibody (2C11) was measured by determining
[3H]thymidine incorporation (see Materials and Methods).
(C) Allogeneic response in a mixed lymphocyte reaction of C57BL/6
splenocytes from ICER-transgenic or nontransgenic control mice to
allogeneic BALB/c splenocytes. Irradiated, unfractionated splenocytes
from syngeneic C57BL/6 or allogeneic BALB/c splenocytes were added to
cultures containing unfractionated ICER-transgenic or nontransgenic
C57BL/6 splenocytes. After 48 h of coincubation, thymidine uptake
was measured as described in Materials and Methods.
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Received September 28, 2000; revised January 13, 2001; accepted January 17, 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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