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,
*
Center for Pulmonary and Infectious Disease Control, and Departments of
Cell Biology and
Medicine, University of Texas Health Center, Tyler, TX 75710;
§
Department of Inflammation/Autoimmune Diseases, Hoffmann-La Roche, Nutley, NJ 07110; and
¶
Department of Pathology, Nanjing Medical University, Nanjing, People’s Republic of China
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production by Mycobacterium
tuberculosis-stimulated PBMC was reduced, the percentages of T
cells expressing IL-12Rß1 and IL-12Rß2 were significantly
decreased, and IL-12Rß2 mRNA expression was also markedly reduced. In
contrast, in pleural fluid and lymph nodes at the site of disease in
tuberculosis patients, in which IFN- production is enhanced,
IL-12Rß2 mRNA expression was also increased. In M.
tuberculosis-stimulated peripheral blood T cells from
tuberculosis patients, anti-IL-10 and anti-TGF-ß enhanced
IL-12Rß1 and IL-12Rß2 expression, and IFN- production. In
M. tuberculosis-stimulated peripheral blood T cells from
healthy tuberculin reactors, recombinant IL-10 and TGF-ß reduced
IL-12Rß1 and IL-12Rß2 expression, as well as IFN- production. In
combination with prior studies showing increased production of TGF-ß
by blood monocytes from tuberculosis patients, this suggests that
increased TGF-ß production is the underlying abnormality that reduces
IL-12Rß1 and IL-12Rß2 expression in tuberculosis. Our findings
provide evidence that IL-12R expression correlates well with IFN-
production in human tuberculosis, and that expression of IL-12Rß1 and
IL-12Rß2 may play a central role in mediating a protective Th1
response. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The second reason to study tuberculosis is that it provides an
excellent model to investigate the relationship between the immune
response and clinical manifestations of disease from intracellular
pathogens. Most persons infected with M. tuberculosis are
healthy tuberculin reactors who develop protective immunity. Patients
with active tuberculosis have severe disease and ineffective immunity,
and M. tuberculosis-stimulated PBMC from tuberculosis
patients show depressed production of the Th1 cytokine IFN-,
compared with healthy tuberculin reactors 2, 3 . Elucidation of the
mechanism for this reduced Th1 response will enhance our understanding
of resistance and susceptibility to disease from intracellular
pathogens, such as viruses, fungi, and protozoa, as strong Th1
responses are central to immunity against these organisms 4, 5, 6, 7, 8 .
Murine and human Th1 clones express mRNA for the IL-12Rß2 subunit, whereas Th2 clones do not 9, 10 . In addition, resistance to Leishmania major infection in mice correlates with increased expression of IL-12Rß1 and IL-12Rß2 11 . To determine whether the reduced systemic Th1 response in tuberculosis is related to IL-12R expression, we measured IL-12R protein and mRNA expression in peripheral blood and at the site of disease in patients with tuberculosis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood was obtained from 9 healthy tuberculin reactors and from 27 HIV-seronegative patients with culture-proven pulmonary tuberculosis who had received less than 2 wk of antituberculosis therapy. By standard chest radiographic criteria, 5 patients had moderately advanced disease, and 22 patients had far advanced disease. Acid-fast stains of sputum were positive in all patients.
Frozen cervical lymph node tissue samples were obtained from five patients whose lymph nodes showed benign follicular hyperplasia and from five HIV-seronegative patients with tuberculous lymphadenitis who had received less than 4 wk of antituberculosis therapy. Pleural fluid and blood were obtained from four patients with tuberculous pleuritis who had received less than 2 wk of antituberculosis therapy.
Abs to IL-12R subunits
The 2B10 Ab to human IL-12Rß1 12 was used. In addition, hybridomas producing anti-human IL-12Rß2 were made by fusing SP2/0 myeloma cells with splenocytes isolated from Lewis rats immunized and boosted with purified recombinant human IL-12Rß2-IgG1 fusion protein. A mAb 2B6 was generated, which binds to the surface of a transfected Ba/F3 cell line that expresses human IL-12Rß2 13 , but not to the parental Ba/F3 cell line or to transfected Ba/F3 cells that express human IL-12Rß1 (D.H.P., unpublished data). Purified 2B6, a rat IgG2a Ab, was produced from ascitic fluid by sequential caprylic acid and ammonium sulfate precipitation 14 .
Cell culture conditions
PBMC and pleural fluid mononuclear cells were isolated by
differential centrifugation over Ficoll-Paque (Pharmacia, Piscataway,
NJ). For patients with tuberculous pleuritis, pleural fluid cells and
PBMC were lysed with 4 M guanidinium isothiocyanate and stored at
-20°C before preparation of RNA. For patients with pulmonary
tuberculosis and for healthy tuberculin reactors, PBMC were plated in 2
ml wells at 4–5 x 106 cells/ml in RPMI (Life
Technologies, Grand Island, NY) containing penicillin/streptomycin
(Life Technologies) and 10% heat-inactivated human serum, in the
presence or absence of 1 µg/ml of heat-killed M.
tuberculosis Erdman strain, kindly provided by Dr. Patrick
Brennan, Colorado State University (Fort Collins, CO). In some
experiments, recombinant IL-10 (10 ng/ml; Genzyme, Cambridge, MA) or
TGF-ß (10 ng/ml; Genzyme) or neutralizing Abs to IL-10 (20 µg/ml;
Biosource International, Camarillo, CA) and to TGF-ß (60 µg/ml;
Genzyme) were also added to the cell cultures. In some experiments,
supernatants were collected after 5 days of culture and stored at
-70°C, before measurement of IFN- concentrations by ELISA
(PharMingen, San Diego, CA).
IL-12R expression by cytofluorometric analysis
After culture for 5 days, PBMC were centrifuged over
Ficoll-Paque to remove dead cells, and cytofluorometric analysis was
performed, using standard methods. Briefly, 2–3 x
105 cells were incubated with 5 µg/ml of 2B6 or 2B10,
followed by 5 µl of a 1/20 dilution of FITC goat anti-rat IgG
(Caltag Laboratories, Burlingame, CA). Control samples were stained
with the secondary Ab only. Representative examples of staining with
anti-IL-12Rß1 and anti-IL-12Rß2 are shown (Fig. 1
).
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IL-12R mRNA expression by competitive RT-PCR
After culture for 3 days, nonadherent cells were removed and incubated with magnetic beads conjugated to CD3 (Dynal, Lake Success, NY). A magnetic cell separator was used to positively select CD3+ cells, which were >98% pure by cytofluorometric analysis. Cells were lysed with 4 M guanidinium isothiocyanate and stored at -20°C before preparation of RNA.
For lymph node specimens, cryostat sections 6 µm thick were lysed with 4 M guanidinium isothiocyanate and stored at -20°C. RNA was prepared from lymph nodes, pleural fluid mononuclear cells, and CD3+ cells by phenol/chloroform extraction, as described 15 . cDNA was synthesized from RNA by standard methods 3 .
To accurately compare cytokine mRNA expression in different specimens, it is critical to use equivalent amounts of substrate cDNA. Because we were interested in measuring IL-12Rß2 mRNA expression by T cells, we normalized all samples for CD3 cDNA content by competitive PCR, as previously described 3 . Briefly, the target CD3 sequence and a competitor DNA construct were coamplified by the 5' primer CTG GAC CTG GGA AAA CGC ATC and the 3' primer GTA CTG AGC ATC ATC TCG ATC. A DNA thermal thermocycler 480 (Perkin-Elmer Cetus, Norwalk, CT) ran 26 cycles of denaturation at 94°C for 1 min and annealing/extension at 65°C for 2 min. PCR product (10 µl) was subjected to electrophoresis on 1.5% agarose gels and visualized by staining with ethidium bromide. For quantifying PCR product, gels were photographed with a SPEEDLIGHT gel documentation system (B/T Scientific Technologies, Carlsbad, CA) and analyzed with QGEL software (Kendrick Laboratories, Madison, WI), an imaging and analysis system that permits accurate comparison of the integrated density of the PCR product bands for target and MIMIC cDNA. By plotting the ratio of integrated density of sample to MIMIC PCR product against the known amount of MIMIC substrate cDNA, the amount of cDNA in each sample was calculated. This method allows accurate detection of twofold differences in substrate cDNA concentrations 3 .
For each sample, aliquots containing equivalent amounts of CD3 cDNA
were used as substrate and amplified by competitive PCR with primers
specific for IL-12Rß2. In some experiments, primers specific for
IL-2R and IFN- were also used. The 5' and 3' primers,
respectively, were as follows: IL-12Rß2, GAG GGA CTG GTA CTG CTT AAT
CGA CTC and CCT CAC ACA GGT TCA TTA TGT TAA TAC GAG TG; IL-2R, CCA
CTC TGT GGA AGT GCT CA and TCC GTT CCA GCC AGA AAT AC; and IFN-, AGT
TAT ATC TTG GCT TTT CAG CTC TGC and CCT CAC CGA ATA ATT AGT CAG CTT
TTC. cDNA was amplified by 35 cycles of denaturation at 94°C for 1
min and annealing/extension at 65°C for 2 min. For IL-12Rß2 cDNA,
the predicted size of the target PCR product was 511 bp and that of the
standard PCR product was 367 bp. For IL-2R cDNA, the predicted size
of the target PCR product was 180 bp, and that of the standard PCR
product was 322 bp. PCR product was quantified by competitive PCR, as
outlined above for CD3. Positive controls containing cytokine receptor
cDNA (from PHA-stimulated PBMC) and negative controls containing no
cDNA were employed in each set of reactions.
Statistical analysis
Data for different groups were expressed as the mean ± SEM, and were compared by the paired or unpaired Student’s t test, as appropriate. For data that were not normally distributed, the Wilcoxon rank-sum test was used.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In freshly isolated PBMC from healthy tuberculin reactors,
20–30% of cells were IL-12Rß1+, compared with only
2–3% of PBMC from tuberculosis patients. In both groups, the
percentages of IL-12Rß1+ cells increased in parallel
during 5 days of culture (Fig. 2A). There was no significant
IL-12Rß2 expression in freshly isolated PBMC from healthy tuberculin
reactors or tuberculosis patients (Fig. 2B). IL-12Rß2
expression was similar in both groups for the first 3 days, but
increased more markedly in healthy tuberculin reactors after day 3.
Subsequent measurements of IL-12R expression for M.
tuberculosis-stimulated PBMC were not made after 5 days of culture
because cell viability decreased after this time point.
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). Similarly, the percentage
of IL-12Rß2+ cells was lower in tuberculosis patients
(10 ± 3 versus 37 ± 3, p < 0.0001).
Expression of IL-12Rß1 and IL-12Rß2 paralleled IFN- production,
as mean IFN- concentrations in supernatants of M.
tuberculosis-stimulated PBMC from tuberculosis patients were lower
than corresponding values in healthy tuberculin reactors (433 ±
105 pg/ml versus 3132 ± 260 pg/ml, p < 0.0001).
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To evaluate IL-12R expression in T cell subpopulations, we
performed single and double immunolabeling with anti-IL-12Rß1 or
anti-IL-12Rß2, in combination with anti-CD3, anti-CD4,
and anti-CD8. In M. tuberculosis-stimulated PBMC, the
percentages of CD3+ cells were similar in tuberculosis
patients and healthy tuberculin reactors (69 ± 6 versus 78
± 6, p > 0.05), as were the percentages of
CD4+ and CD8+ cells (data not shown). In three
healthy tuberculin reactors and six tuberculosis patients, the
percentages of CD3+ cells that expressed IL-12Rß1 and
IL-12Rß2 were depressed in tuberculosis patients (Fig. 4, p = 0.003 and 0.001,
respectively). The percentages of CD4+ cells expressing
IL-1Rß1 and IL-1Rß2 were also depressed in tuberculosis patients
(p = 0.02 and p = 0.0001,
respectively). In contrast, the percentages of CD8+ cells
expressing IL-12Rß1 and IL-12Rß2 were similar in healthy
tuberculin reactors and tuberculosis patients
(p > 0.05).
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To determine whether depressed expression of IL-12R in M.
tuberculosis-stimulated PBMC of tuberculosis patients was mediated
by changes in transcription or stability of IL-12R mRNA, we determined
mRNA levels by competitive RT-PCR. Amplification of IL-12Rß1 cDNA was
unsatisfactory, despite the use of multiple primer pairs and reaction
conditions. However, amplification of IL-12Rß2 cDNA was achieved.
Consistent with the data obtained by immunolabeling, IL-12Rß2 mRNA
was undetectable or expressed at very low levels in freshly isolated
PBMC from tuberculosis patients or from healthy tuberculin reactors
(data not shown). After stimulation of PBMC with M.
tuberculosis, T cells were isolated by immunomagnetic selection
and IL-12Rß2 mRNA was determined (Fig. 5). IL-12Rß2 mRNA expression was
greatly reduced in 9 of 11 tuberculosis patients (mean 0.30 ±
0.14 x 10-3 attoM, compared with 1.5 ±
0.3 x 10-3 attoM in healthy tuberculin reactors,
p < 0.001). Reduced expression of IL-12Rß2 mRNA did
not reflect generalized depression of cytokine receptors in
tuberculosis, as expression of IL-2R mRNA was not different in
tuberculosis patients and healthy tuberculin reactors (Fig. 5).
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Although the Th1 response is depressed in the peripheral blood of
tuberculosis patients, IFN- mRNA and protein are selectively
increased in lungs, lymph nodes, and pleural fluid of patients with
tuberculosis 16, 17, 18 . Competitive RT-PCR confirmed increased
expression of IFN- mRNA in lymph nodes from tuberculosis patients,
compared with those showing benign follicular hyperplasia (Fig. 6). To determine whether changes in
IL-12Rß2 paralleled those of IFN-, we evaluated IL-12Rß2 mRNA
expression at the site of disease. In lymph nodes from five
tuberculosis patients, IL-12Rß2 mRNA expression was 50-fold higher
than in lymph nodes from patients with benign follicular hyperplasia
(Fig. 6, mean of 6.9 ± 2.6 x 10-3 attoM for
tuberculosis versus 0.14 ± 0.03 x 10-3 attoM
for benign follicular hyperplasia, p = 0.01, Wilcoxon
rank-sum test). In contrast, expression of IL-2R mRNA was similar in
lymph nodes from patients with or without tuberculosis (Fig. 6).
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).
IL-12Rß2 mRNA expression was greater in pleural fluid cells (mean
0.37 ± 0.07 x 10-3 attoM, compared with
0.13 ± 0.06 x 10-3 attoM for PBMC). Expression
of IL-2R mRNA was similar in pleural fluid and blood (Fig. 7). In
confirmation of previous work 18 , IFN- mRNA expression was also
greater in pleural fluid cells (mean 20.2 ± 2.2 x
10-3 attoM versus 5.6 ± 0.3 x
10-3 attoM for PBMC).
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In response to M. tuberculosis, mononuclear phagocytes
produce IL-10 and TGF-ß 15, 19, 20 , both of which inhibit IFN-
production in response to mycobacterial Ags 21, 22, 23, 24 . IL-12 enhances
IL-12Rß2 mRNA expression in human and murine T cell clones 9, 10 .
IL-10 and TGF-ß decrease production of IL-12 25, 26 , and may
therefore reduce IL-12R expression by T cells. To determine whether
IL-10 and/or TGF-ß contributed to reduced IL-12Rß1 and IL-12Rß2
expression by peripheral blood T cells in tuberculosis patients,
neutralizing Abs to IL-10 and TGF-ß were added to M.
tuberculosis-stimulated PBMC from three tuberculosis patients.
Addition of anti-IL-10 or anti-TGF-ß increased IL-12Rß1
expression 2- to 3-fold and increased IL-12Rß2 expression 3- to
10-fold (Fig. 8).
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concentrations in supernatants of
M. tuberculosis-stimulated PBMC from tuberculosis patients
were increased from 296 ± 111 pg/ml to 1213 ± 64 pg/ml with
addition of anti-IL-10, and to 1117 ± 65 pg/ml with addition
of anti-TGF-ß. These results suggest that IL-10 and TGF-ß
contribute to reduced expression of IL-12R and IFN-.
To directly demonstrate the effects of IL-10 and/or TGF-ß on IL-12R
expression by peripheral blood T cells in tuberculosis patients, we
added these cytokines to M. tuberculosis-stimulated PBMC
from healthy tuberculin reactors. In three experiments, IL-10 reduced
IL-12Rß2 expression by 76–85%, and TGF-ß reduced IL-12Rß2
expression by 48–84% (Fig. 9B). IL-10 and TGF-ß also
reduced IL-12Rß1 expression (Fig. 9A), but the reduction
was less striking than that observed for IL-12Rß2. Parallel to the
changes observed for IL-12Rß2 protein, IL-10 and TGF-ß reduced
IL-12Rß2 mRNA expression by 30–76% (data not shown). In addition,
consistent with prior studies, mean IFN- concentrations in
supernatants of M. tuberculosis-stimulated PBMC from four
healthy tuberculin reactors were reduced from 2909 ± 489 pg/ml to
1666 ± 336 pg/ml with addition of IL-10, and to 1359 ± 469
pg/ml with addition of TGF-ß.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in human tuberculosis. In
M. tuberculosis-stimulated peripheral blood T cells,
IL-12Rß1 and IL-12Rß2 expression were reduced in tuberculosis
patients with reduced IFN- production, compared with healthy
tuberculin reactors with normal IFN- production. In contrast, at the
site of disease in patients with tuberculous pleuritis and
lymphadenitis, in which IFN- production is enhanced 17, 18 ,
IL-12Rß2 mRNA expression was increased in vivo. Addition of
anti-IL-10 or anti-TGF-ß to M.
tuberculosis-stimulated peripheral blood T cells from tuberculosis
patients enhanced expression of IL-12Rß1 and IL-12Rß2, and IFN-
production. Conversely, addition of recombinant IL-10 or TGF-ß to
M. tuberculosis-stimulated PBMC from healthy tuberculin
reactors decreased expression of IL-12Rß1 and IL-12Rß2, as well as
IFN- production. These findings provide evidence that IL-12Rß1 and
IL-12Rß2 expression correlate tightly with IFN- production in
human disease from an intracellular pathogen, and suggest a
relationship between expression of IL-12R and a protective Th1
response.
Host defenses against most intracellular pathogens are mediated by Th1
cells that produce IFN-, and severe manifestations of disease are
generally associated with a reduced Th1 response. In extensive disease
due to Mycobacterium leprae or Leishmania,
depressed Th1 responses probably result from enhanced production of the
Th2 cytokines IL-4 and IL-10 8, 27, 28, 29, 30 , which inhibit development of
Th1 cells that produce IFN- 31 . In diseases due to other
intracellular pathogens such as Listeria monocytogenes,
Salmonella, and M. tuberculosis, a reduced Th1
response is associated with severe disease, but there is no increase in
the Th2 response 3, 17, 32, 33 . In these situations, a potential
mechanism for diminished Th1 responses is through reduced effects of
IL-12, which is a central initiator of Th1 responses 34, 35 . For
example, in some patients with familial susceptibility to disseminated
Mycobacterium avium complex infection, IL-12 production by
blood monocytes is reduced 36 .
An alternative mechanism by which Th1 responses to intracellular
pathogens are depressed is through reduced expression of IL-12R, which
would decrease IFN- production in response to IL-12. In mice with
enhanced susceptibility to Leishmania, expression of
IL-12Rß1 and IL-12Rß2 was reduced, as was IFN- production in
response to IL-12 11 . In humans, IL-12Rß1 deficiency was recently
described in seven patients with severe manifestations of mycobacterial
infection 37, 38 . PBMC from these patients also failed to produce
IFN- in response to IL-12. The current findings extend these
observations to a much larger population, demonstrating that decreased
expression of IL-12Rß1 and IL-12Rß2 is characteristic of systemic T
cells in tuberculosis patients. In these patients, M.
tuberculosis-induced production of IFN- by T cells is
depressed, but blood monocytes produce normal amounts of IL-12 and
IL-10 24, 39 , suggesting that T cells have reduced responsiveness to
IL-12. Addition of IL-12 to M. tuberculosis-stimulated PBMC
markedly increases IFN- production 24 , indicating that IL-12
responsiveness is partially restored by exogenous IL-12. These findings
can now be explained by reduced IL-12Rß1 and IL-12Rß2 expression in
T cells from tuberculosis patients, which diminishes responsiveness to
IL-12. Addition of IL-12 up-regulates IL-12R expression, restores
responsiveness to IL-12, and increases IFN- production 22, 24 .
Several lines of evidence suggest that excess production of TGF-ß may
contribute to reduced IL-12R expression in tuberculosis. TGF-ß can
down-regulate IL-12Rß2 expression and IL-12-mediated signal
transduction in murine T cells, resulting in reduced IFN- production
in response to IL-12 40, 41 . In addition, blood monocytes from
tuberculosis patients produce high concentrations of TGF-ß 22, 42 ,
and the current study shows that anti-TGF-ß enhances IL-12R
expression and IFN- production by M.
tuberculosis-stimulated T cells from tuberculosis patients. We
therefore speculate that enhanced TGF-ß production is the underlying
abnormality that reduces IL-12R expression in tuberculosis. An
alternative possibility is that Ag-reactive cells with increased IL-12R
expression are recruited to the site of disease, reducing IL-12R
expression in PBMC. Additional studies are needed to understand the
mechanism underlying the depressed Th1 response in tuberculosis and in
other diseases due to intracellular pathogens.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Peter F. Barnes, Center for Pulmonary and Infectious Disease Control, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708-3154. E-mail address:
Received for publication August 28, 1998. Accepted for publication November 10, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Immunol. 155:785.[Abstract]
interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis. Infect. Immun. 63:3514.[Abstract]
or interleukin 4 during the resolution or progression of murine leishmaniasis: evidence for expansion of distinct helper T cell subsets. J. Exp. Med. 169:59. production. Proc. Natl. Acad. Sci. USA 93:3193. production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041. production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation. J. Immunol. 157:411.[Abstract]
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