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* Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94141;
Department of Medical Biochemistry, University of Oslo, Oslo, Norway; and
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain (2, 3). Zap-70 tyrosine phosphorylates lipid raft-associated adaptor
molecules such as the linker for activation of T cells (4, 5), which further recruit several downstream Src homology 2
domain-containing signaling molecules (6, 7, 8). The assembly
of TCR signaling complexes occurs in specialized membrane microdomains
with high cholesterol and glycolipid contents called
glycosphingolipid-enriched microdomains or lipid rafts (reviewed in
Refs. 9, 10). Rafts also serve as a scaffold for
assembly of a recently unraveled inhibitory pathway which involves
protein kinase A
(PKA)3 type I that in
response to cAMP activates the C-terminal Src kinase (Csk) by
phosphorylation of residue S364 (11). Activated Csk
subsequently phosphorylates the C-terminal inhibitory tyrosine residue
in Lck and thereby acts as a negative regulator of TCR signaling
(12, 13, 14). This may be an important mechanism whereby
cAMP-inducing ligands such as PGE and 
-adrenergic stimuli inhibit
mitogenic signaling pathways and regulate set-point for activation of T
cells. However, cAMP negatively regulates signaling events at multiple
levels (15). In addition to ligand-receptor interaction,
production of cAMP may also be induced during T cell activation or by
intracellular events not involving engagement of transmembrane
receptors and contribute to termination of the activating signal, but
such mechanisms remain to be elucidated.
The role of the cAMP-PKA type I pathway as a potent inhibitory
regulator has not been clearly defined functionally in the different
immune responses in CD4 and CD8 T cells, nor has it been defined in the
context of Ag-specific immune functions. In this study, we have
investigated the effect of PKA type I on production of IFN-
,
TNF-
, IL-2, and IL-4 as well as proliferation of T cells with
various Ags. We report that PKA type I acts as a consistent and
universal inhibitor of T cell function, reducing the population of
cytokine-expressing cells as well as inhibiting proliferation in a
concentration-dependent manner.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMC from healthy blood donors (n = 13) were isolated from heparinized whole blood by Ficoll-Paque PLUS density gradient centrifugation (Amersham Pharmacia Biotech, Uppsala, Sweden), and washed twice in RPMI 1640 (Life Technologies, Grand Island, NY) with 15% fetal calf serum. When used, peripheral human T cells were purified by negative selection (16). All experiments were performed with freshly isolated PBMC or T cells.
Reagents
Sp-8-bromo-cAMP-phosphorothioate (Sp-8-Br-cAMPS) and Rp-8-bromo-cAMP-phosphorothioate (Rp-8-Br-cAMPS; BioLog Life Sciences, San Diego, CA) were dissolved to stock concentrations of 10 mM in PBS (Life Technologies). PGE2, 3-isobutyl-1-methylxanthine (IBMX), and rolipram were purchased from Sigma-Aldrich (St. Louis, MO) and dissolved to stock concentrations in DMSO.
Ags and Abs
Staphylococcal enterotoxin B (SEB; Sigma-Aldrich) was dissolved
to a stock concentration of 100 µg/ml in PBS. A final concentration
of 10 µg/ml was used in all intracellular cytokine flow cytometry
assays, while a final concentration of 100 ng/ml was used in the CFSE
dilution proliferation assays. CMV lysates and matched control Ag
(BioWhittaker, Walkersville, MD) were used at a 1/12.5 dilution. For
CD8+ T cell responses, PBMC were stimulated with
a HLA-A*0201 epitope of CMVpp65 (residues 495–503) at a final
concentration of 5 µg/ml. Tuberculin purified protein derivative
(PPD; Statens Seruminstitut, Copenhagen, Denmark) was used at a final
concentration of 10 µg/ml. For cell surface and intracellular
cytokine staining, different combinations of mouse anti-human mAbs
were used: CD3 FITC, PerCP and allophycocyanin, CD4 PerCP and
allophycocyanin, CD8 PerCP and allophycocyanin, CD69 FITC, IFN- PE,
TNF- PE, IL-2 PE, and IL-4 PE (BD Biosciences, Mountain View,
CA).
Intracellular cytokine staining assay
Freshly isolated PBMC were preincubated with cAMP analogs or cAMP-inducing pharmacological compound 1 h before stimulation with Ag. The cells were then incubated for 1 h if not otherwise noted before addition of brefeldin A (Sigma-Aldrich) at a final concentration of 10 µg/ml and incubation for another 5 h. The cells were washed in PBS, 0.02% EDTA, and 1% BSA, fixed, and permeabilized in FACS permeabilizing buffer (BD Biosciences) for 10 min. After washing, staining was performed with a mixture of FITC-, PE-, PerCP-, and allophycocyanin-conjugated Abs for 30 min at 4°C in the dark before subsequent washing, fixing, and flow cytometry analysis using a BD Biosciences FACSCalibur instrument.
ELISPOT assay
Each well of a sterile multiscreen 96-well filtration plate
(Millipore MAHAS4510; Millipore, Bedford, MA) was coated with 50
µl anti-IFN- mAb (Mabtech, Stockholm, Sweden) at a
concentration of 5 µg/ml in 1 M sodium bicarbonate buffer (pH 9.5).
After an overnight incubation at 4°C, each well was washed four times
with PBS (Cellgro, Herndon, VA) and blocked with 50 µl 5% pooled
human serum in RPMI 1640 for 1 h at 37°C. A total of
2.0 x 105 PBMC was added to each well, and
SEB was added at a concentrations of 1.0 ng/ml. After incubation
overnight (14 h) at 37°C, plates were washed four times using PBS
with 0.05% Tween 20 (FisherBiotech, Fair Lawn, NJ). Biotinylated
anti-IFN- mAb 7-B6-1 (MabTech) was added at 1 µg/ml in 50 µl
PBS and the plate was incubated for 2 h at 37°C. Next, plates
were washed four times using 0.1% Tween 20 in PBS and then treated
with avidin-conjugated HRP H (Vector Laboratories, Burlingame, CA).
After 1 h, plates were washed four times with 0.1% Tween 20 in
PBS. Fifty microliters of stable diaminobenzidine tetrahydrochloride
substrate (Research Genetics, Hunstville, AL) was added to each well
for 5 min and then washed away with water. IFN- spot-forming cells
were visualized and counted using an AID ELISPOT reader system
(Autoimmun Diagnostika, Strassburg, Germany). Raw counts were
standardized to express the frequency of spot-forming cells per
million PBMC.
CFSE proliferation assay
Fresh PBMC were resuspended at a concentration of 107 cells/ml in RPMI 1640 and labeled with CFSE (Molecular Probes, Eugene, OR) by incubation for 10 min in 37°C/5% CO2 at a final concentration of 2 µM. Labeling was quenched with RPMI 1640 supplemented with 15% FCS and the cells were washed twice before culturing in flat-bottom 96-well plates. FACS analysis was performed after 96 h of incubation. In the assays where CFSE labeling was combined with staining for intracellular cytokines, brefeldin A was added for the last 6 h, the cells were then transferred to V-bottom 96-well plates, and the procedure for intracellular cytokine staining was conducted before FACS analysis.
Assessment of Csk activity
Purified peripheral T cells (40 x
106 cells/ml in RPMI 1640) were incubated at
37°C for 30 min with or without the cAMP analog Sp-8-Br-cAMPS at
indicated concentrations. Thereafter, cells were disrupted in lysis
buffer (50 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM EDTA, 1% Triton X-100,
50 mM n--octyl-glucoside, 10 mM
NaPPi, 1 mM
Na3VO4, 50 mM NaF, and 1 mM
PMSF) and subjected to immunoprecipitation with anti-Csk Ab
(catalog no. Sc-286; Santa Cruz Biotechnology, Santa Cruz, CA). After
overnight incubation at 4°C, protein A-Sepharose was added and the
incubation was continued for 1 h. Immune complexes were washed
three times in lysis buffer and three times in Csk kinase assay
buffer (50 mM HEPES and 5 mM MgCl2, pH 7.4),
followed by Csk kinase assays and Western blot analysis. The tyrosine
kinase activity of human Csk was measured as incorporation of
[32P]phosphate into the synthetic polyamino
acid poly(Glu,Tyr) 4:1 (Sigma-Aldrich). A standard protocol was
followed with reaction volumes of 50 µl containing HEPES buffer (pH
7.4), 5 mM MgCl2, 200 µM
[-32P]ATP (0.15 Ci/mmol), 200 µg/ml
poly(Glu,Tyr), and immunoprecipitated Csk. The incubation temperature
was 30°C, and the incubation time was 12 min.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To explore possible effects of cAMP and PKA type I on early
functional events in immune activation, we measured the expression of
the activation marker CD69 and production of IFN- after activation
of PBMC with the superantigen SEB for 6 h. The expression of CD69
and IFN- were measured by flow cytometry in the presence and absence
of the PKA agonist Sp-8-Br-cAMPS alone or in combination with the PKA
type I selective antagonist Rp-8-Br-cAMPS. The cells were preincubated
with cAMP analogs for 1 h to allow diffusion of the compounds,
followed by activation with SEB. Brefeldin A was then added 1 h
after activation with SEB, and the cultures were incubated for 5 h
for cytokine accumulation.
The expression of both CD69 and IFN- were markedly reduced by
preincubation with 250 µM Sp-8-Br-cAMPS (agonist) in
CD3+ T cells compared with control (Fig. 1
, a and b). To
clarify whether this inhibited cytokine production is mediated through
PKA type I, associated with the TCR/CD3 and lipid rafts, or PKA type
II, whose localization is mainly confined to the perinuclear and Golgi
centrosomal regions in lymphocytes (17), we preincubated
the cells with 250 µM Sp-8-Br-cAMPS in combination with 1000 µM of
the PKA type I selective antagonist Rp-8-Br-cAMPS (Fig. 1c).
The antagonist reversed almost completely the inhibitory effect of the
agonist, indicating that the inhibitory effect of cAMP in the early T
cell activation is mainly due to activation of PKA type I. The
antagonist had no effect on CD69 and IFN- expression alone (Fig. 1d).
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To investigate whether the inhibitory effect of cAMP and PKA type
I was due to induction of apoptosis, we evaluated the morphology of
unstimulated and SEB-stimulated PBMC with and without preincubation
with 1000 µM Sp-8-Br-cAMPS and with and without incubation with
brefeldin A for the last 5 h of the incubation time by flow
cytometry on forward and side scatter. The cultures were incubated for
various periods of time ranging from 6 to 48 h and did not
demonstrate the morphological changes characteristic of apoptosis, with
decrease in forward scatter and increased side scatter, in the presence
of the cAMP analog (data not shown). Furthermore, apoptosis was also
assessed by Annexin VFITC labeling under the same
experimental conditions (Fig. 2, culture
incubated for 24 h is shown). The cAMP agonist did not induce any
significant increase in annexin V binding as a marker of apoptotic
cells in the resting (Fig. 2, a and b) or
activated cultures (Fig. 2, c and d). In
contrast, anisomycin used as control (Fig. 2, e and
f) induced apoptosis and increased annexin V binding in both
unstimulated and activated cultures. Similar data were obtained by
propidium iodide exclusion (data not shown).
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,
TNF-, IL-2, and IL-4
To examine whether the effects of cAMP and PKA type I were
specific for IFN- expression, we measured the expression of various
cytokines after SEB activation of PBMC with increasing concentrations
of Sp-8-Br-cAMPS. We found that expression of all cytokines examined
(IFN-, TNF-, IL-2, and IL-4) was reduced in a
concentration-dependent manner by the cAMP analog (Fig. 3a), although the sensitivity
to inhibition by the cAMP analog varied among the cytokines. In all
cases, the cAMP-mediated inhibition was reversible with the PKA type I
selective antagonist Rp-8-Br-cAMPS. We next measured the level of
inhibition of cytokine expression with longer cytokine accumulation
periods to see whether the effect was transient. Accumulation periods
of 5, 15, and 25 h were conducted, and the level of inhibition was
persistent and concentration dependent at all of these time points
(data not shown).
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production and, as shown in Fig. 3
b, similar results were
obtained. Increase in endogenous cAMP by physiological agonists and pharmacological agents also inhibits cytokine production
The effect of PGE2 on SEB-induced IFN-
expression was assessed by intracellular flow cytometry in the presence
and absence of 1000 µM Rp-8-Br-cAMPS. PGE2
increased endogenous cAMP production through E2
and E4 receptors on T cells and inhibited
cytokine production as shown in Fig. 4.
In addition, IBMX and rolipram, which are nonselective and type
4-specific phosphodiesterase inhibitors, respectively, that inhibit
degradation of endogenous cAMP, also inhibited IFN- release. The PKA
type I selective antagonist fully or partially reversed the inhibitory
effect of the various compounds (Fig. 4).
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To further address the question of which T cell compartment is
affected by cAMP in the inhibition of immune activation, we
investigated the effects of cAMP and PKA type I on CD4 and CD8 T cells.
As shown in Fig. 5, a and
b, the expression of both IFN- and TNF- was inhibited
in a concentration-dependent manner. However, this experiment was
performed with SEB stimulation of PBMC containing APC. To eliminate the
possibility that the effects observed could be due to suppressive
effects of cAMP on the function of APC, we isolated APC by adherence
and loaded the cells with SEB followed by paraformaldehyde fixation. We
then set up an autologous coculture with fixed, Ag-loaded APC, and an
APC-depleted PBMC population at a 1:10 ratio. The coculture was
incubated for 6 h before addition of brefeldin A. Cytokine
accumulation was allowed to proceed for 14 h. The expression of
IFN- was assessed by intracellular flow cytometry in CD4 and
CD8 T cells and a concentration-dependent inhibition of cytokine
expression was observed with increasing concentrations of Sp-8-Br-cAMPS
showing that inhibition is independent of APC (Fig. 5c).
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To further determine the extent of the cAMP-mediated inhibition of
immune functions, we investigated the effects on proliferation of CD3,
CD4, and CD8 T cells by the CFSE dilution assay. As Fig. 6a shows, a
concentration-dependent decrease in SEB-induced proliferation with
increasing concentrations of Sp-8-Br-cAMPS is observed in all three
cell populations. The inhibition was reversible with the PKA type I
selective antagonist Rp-8-Br-cAMPS (data not shown).
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b, there is a sequential reduction
of CFSE fluorescence intensity for each cell division, with the highest
fraction of IFN--expressing T cells being in the later daughter cell
generations. With increasing concentrations of Sp-8-Br-cAMPS, there was
a profound reduction in IFN- expression and a marked suppression of
proliferation shown by disappearance of the last two cell divisions
with 1000 µM Sp-8-Br-cAMPS. cAMP and PKA type I inhibits Ag-specific immune responses
We next examined the effect of cAMP and PKA type I on Ag-specific
immune responses (Fig. 7a). As
seen with SEB-induced immune responses, we observed a
concentration-dependent inhibition of CMV-induced IFN- expression by
increasing concentrations of Sp-8-Br-cAMPS in both the CD4 and CD8 T
cell populations. To induce optimal stimulation, the CD4 T cell
population was stimulated by CMV-infected cell extracts, while the CD8
T cell population was stimulated by CMVpp65. The range of inhibition
was from 60 to 80% in both cell populations.
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production by
combining the CFSE dilution assay with intracellular flow
cytometry (Fig. 7b). As observed with the SEB- and
CMV-induced immune responses, the T cell proliferation as well as
IFN- expression induced by tuberculin PPD declined in a
concentration-dependent manner with Sp-8-Br-cAMPS. Furthermore, both T
cell proliferation and IFN- expression were fully reversible with
the cAMP antagonist Rp-8-Br-cAMPS (data not shown). cAMP activates Csk
To assess the effect the cAMP agonist used in this study on the
previously mapped mechanism for cAMP-PKA inhibition of T cell functions
(11), we examined whether Sp-8-Br-cAMPS lead to an
increase in Csk activity. Csk phosphotransferase activity was assessed
in vitro after treatment with increasing concentrations with the cAMP
analog resulting in a concentration-dependent increase in Csk activity
with a >2-fold increase in the activity with the highest concentration
used (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNF-,
IL-2, and IL-4 in a dose-dependent manner. The inhibition involved both
CD4 and CD8 T cells, and the effect was independent of APC and did not
induce apoptosis. Furthermore, the cAMP analog inhibited both
SEB-induced proliferation and Ag-specific immune responses to CMV and
tuberculin PPD. Coincubation with Rp-8-Br-cAMPS, which is a selective
inhibitor of PKA type I, completely reversed the inhibitory effect of
the PKA agonist Sp-8-Br-cAMPS. This indicates that the effects observed
are due to activation of PKA type I and that inhibition of T cell
function following cAMP incubation can be reversed in a timely manner
with a cAMP antagonist. In our experiments, the sensitivity to cAMP varied among the cytokines. This may be due to different thresholds for inhibition or different kinetics. However, different accumulation periods revealed a consistent inhibition, indicating that the inhibitory function is not a transient effect which is overcome or bypassed later in the activation process. Thus, the different sensitivities observed may rather be due to distinct pathways being involved in the transcriptional activation of the various cytokines downstream of the initial activation process.
We also investigated the effects of cAMP and PKA type I on Ag-driven T cell proliferation. Clonal expansion and proliferation are the basis for establishment of an adequate and efficient immune response. Recent studies have shown that effector functions of Ag-specific T lymphocytes can be segregated and may be independently regulated (18). In hepatitis B infection, immunological clearance appears to predominantly mediated by cytokine release rather than direct cell lysis of hepatitis B virus-infected cells (19). In this study, we find that the proliferation and cytokine production of effector T cells can be segregated based upon the dosage of Sp-8-Br-cAMPS used. At the highest concentration of compound (1000 µM), both proliferation and cytokine production were suppressed whereas at a concentration of 250 µM, T cells proliferated but did not produce cytokine.
Finally, we investigated whether cAMP agonist treatment leads to an activation of Csk activity in the T cells. We have previously shown that cAMP through activation of PKA type I leads to an activation of Csk in the lipid raft fraction of the cell membrane (11). Csk inhibits T cell activation by phosphorylating Lck on residue Y505, leading to a conformational change and inactivation of the enzyme. We report here that the cAMP compound used in this study (Sp-8-Br-cAMPS) leads to a dose-dependent increase in Csk activity. This points to Csk as an early target for cAMP-induced inhibition of T cell activation specifically acting through PKA type I, although additionally other targets downstream for the initial activation events may be involved.
Specific manipulation of aberrant T cell activity in autoimmune
disease, transplantation, or delayed-type hypersensitivity is a long
sought after clinical goal. Current strategies for immunosuppression
can be divided into separate categories depending upon mode of action
of the therapeutic agent. First, lymphocyte cell division can be
interrupted with drugs such as azathioprine, cyclophosphamide, or
mycophenolic acid. Second, lymphocyte depletion can be achieved through
drugs which produce lysis and/or inactivation (monoclonal OKT3
antilymphocyte Abs or thymoglobulin). Third, interruption of lymphocyte
maturational events may be obtained by the calcineurin-inhibiting
agents cyclosporine or tacrolimus (FK506) or with rapamycin. Fourth,
the accessory signals generated by APC can be interrupted by distinct
agents, including the receptor conjugate CTLA4-Ig and anti-B7
or anti-CD40 ligand mAbs. Finally, there are strategies which
specifically target Ag-reactive T cells such as by blocking CD8 binding
using 3 domain mutants of MHC class I-peptide complexes
(20). In organ transplantation, cyclosporine and
tacrolimus (FK506) have been used in clinical practice. These agents
are potent, but nonselective and long-term sequelae of their use
include serious side effects as posttransplant lymphoproliferative
disease associated with broad-spectrum immunosuppression
(21). Other agents under evaluation such as FTY720 induce
apoptosis of T cells, leading to protracted loss of lymphocytes
(22). The need for selective and reversible inhibitors of
T lymphocyte function remains. Further investigation of the
immunosuppressive properties of PKA type I by cAMP analogs is therefore
warranted.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Einar Martin Aandahl, Gladstone Institute of Virology and Immunology, University of California, 365 Vermont Street, San Francisco, CA 94103. E-mail address: maandahl{at}gladstone.ucsf.edu
3 Abbreviations used in this paper: PKA, protein kinase A; Csk, C-terminal Src kinase; Sp-8-Br-cAMPS, Sp-8-bromo-cAMP-phosphorothioate; Rp-8-Br-cAMPS, Rp-8-bromo-cAMP-phosphorothioate; IBMX, 3-isobutyl-1-methylxanthine; SEB, staphylococcal enterotoxin B; PPD, purified protein derivative.
Received for publication February 14, 2002. Accepted for publication May 14, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunits and the CD3 , 
and 
chains. Eur. J. Immunol. 26:1063.[Medline]
subunit of the T-cell receptor. Arch. Biochem. Biophys. 342:117.[Medline]
1 with phosphorylated LAT tyrosine residues: effect of LAT tyrosine mutations on T cell antigen receptor-mediated signaling. J. Biol. Chem. 275:23355.1-binding phosphotyrosyl protein pp36/38. J. Biol. Chem. 270:20177.3 domain mutants of MHC class I/peptide complex. Immunity 14:591.[Medline]
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