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Previous Article | Next Article 
Infection and Immunity, May 2001, p. 3497-3501, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3497-3501.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Contribution of CD8+ T Cells to Gamma
Interferon Production in Human Tuberculosis
Homayoun
Shams,1
Benjamin
Wizel,1,2
Stephen
E.
Weis,3
Buka
Samten,1 and
Peter F.
Barnes1,4,5,*
Center for Pulmonary and Infectious Disease
Control,1 Departments of
Immunology,2
Medicine,4 and Cell
Biology,5 University of Texas Health Center,
Tyler, and Department of Internal Medicine, University of North
Texas Health Sciences Center, Fort Worth,3 Texas
Received 28 September 2000/Returned for modification 22 November
2000/Accepted 20 February 2001
 |
ABSTRACT |
The proportions of peripheral blood mononuclear cells (PBMC),
CD4+ T cells, and CD8+ T cells that produce
gamma interferon (IFN-
) in response to Mycobacterium
tuberculosis were markedly reduced in tuberculosis patients,
particularly in those with severe disease. Depletion of
CD4+ but not CD8+ cells prior to stimulation of
PBMC with M. tuberculosis abolished IFN- production.
These results show that (i) IFN- production by CD8+ and
CD4+ cells correlates with the clinical manifestations of
M. tuberculosis infection and (ii) IFN- production by
CD8+ cells depends on CD4+ cells.
| |
TEXT |
Gamma interferon (IFN-) is
believed to play a central role in immunity against tuberculosis, and
IFN- production by peripheral blood mononuclear cells (PBMC)
correlates with the clinical manifestations of tuberculosis.
Mycobacterium tuberculosis-induced IFN- production by
PBMC is high in healthy tuberculin reactors infected with M. tuberculosis but is reduced in patients with pulmonary
tuberculosis (6, 11, 22, 26), particularly in those with
severe disease (15). CD4+ T cells are
considered to be the predominant source of IFN-, and one study
suggested that the percentage of CD4+ cells producing
IFN- was reduced in tuberculosis patients (3). However,
limited information is available on the contribution of
CD8+ T cells to IFN- production in human tuberculosis
(8, 24). To investigate this question, we used the
enzyme-linked immunospot (ELISPOT) method to measure the frequency of
IFN--producing cells in PBMC, CD8+ cells, and
CD4+ cells from tuberculin-positive and tuberculin-negative
healthy donors, as well as from patients with pulmonary tuberculosis.
Study subjects.
Blood was obtained from 15 healthy donors (9 tuberculin positive and 6 tuberculin negative) and 15 human
immunodeficiency virus-seronegative patients with culture-proven
pulmonary tuberculosis who had been treated for less than 4 weeks. Nine
patients had moderately advanced tuberculosis and six had far advanced
tuberculosis, based on standard chest radiographic criteria
(10). The extent of interstitial or alveolar infiltrate in
both lungs was expressed as a percentage of the volume of one lung.
Moderately advanced tuberculosis was considered to be present if all
three of the following criteria were satisfied: (i) dense alveolar
infiltrate occupied less than one-third of the volume of one lung, (ii)
interstitial infiltrate occupied less than the volume of one lung, and
(iii) the total diameter of cavities was less than 4 cm. Far advanced tuberculosis was defined as disease that was more extensive than moderately advanced tuberculosis.
Cell culture.
PBMC were obtained by centrifugation over
Ficoll-Paque (Pharmacia, Uppsala, Sweden). CD4+ or
CD8+ cells were isolated from PBMC, using positive
selection with magnetic beads conjugated to anti-CD4 or anti-CD8
(Miltenyi Biotech, Auburn, Calif.) (25). In some cases,
PBMC were depleted of CD4+ or CD8+ cells by
negative selection.
PBMC were cultured in T-25 flasks at 106 cells/ml in RPMI
1640 with 10% heat-inactivated human serum. Cells were stimulated with
1 µg of phytohemagglutinin (PHA) per ml or 1 µg of heat-killed M. tuberculosis Erdman strain organisms (whole washed cells)
per ml (equivalent to approximately 2 × 107
bacilli/ml) or were left unstimulated. In preliminary time course studies, the maximum number of spots was detected when PBMC were stimulated with heat-killed M. tuberculosis for 72 h or
with PHA for 48 h. At these time points, supernatants were
collected for measurement of IFN-, and cells were washed three
times. One aliquot of cells was used for the ELISPOT assay, as outlined
below. From two other aliquots, positively selected CD4+
and CD8+ cells were also used in the ELISPOT assay.
In some experiments, PBMC, CD4-depleted PBMC, and CD8-depleted PBMC
were cultured as outlined above, either unstimulated or stimulated with
PHA or heat-killed M. tuberculosis. Supernatants were
collected for measurement of IFN-, and cells were washed three times
and plated for the ELISPOT assay.
IFN- production.
The ELISPOT assay was performed by
incubating stimulated cells for 16 to 18 h in 96-well
nitrocellulose-backed plates, using anti-human IFN- monoclonal
antibodies (1-DIK and 7-B6-1; Mabtech, Nacka, Sweden), according to the
manufacturer's instructions. The spots in air-dried plates were
counted using a stereomicroscope. The images of dried plates were
captured with a scanner (Hewlett-Packard ScanJet 6390C), saved in
tagged image file format, and analyzed with an image analysis program
available from the National Institutes of Health
(http://rsb.info.nih.gov/nih-image/about.html). The histogram
option was used to measure the density of spots in triplicate wells.
The highest values from the wells with unstimulated PBMC were
considered to be background and were deducted from values of stimulated
cells on the same plate.
IFN- concentrations were measured by enzyme-linked immunosorbent
assay, using pairs of antibodies (PharMingen, San Diego, Calif.),
according to the manufacturer's instructions.
Statistical analysis.
Differences between groups were compared
by Student's t test or by analysis of variance, as
appropriate, using the Prism software program (GraphPad Software, Inc.,
San Diego, Calif.). Posttests were used to determine if linear trends
were present among the three groups of persons infected with M. tuberculosis (healthy tuberculin reactors, patients with
moderately advanced tuberculosis, and patients with far advanced tuberculosis).
Frequency of IFN--producing cells in M. tuberculosis-stimulated PBMC.
Using the ELISPOT assay, the
median frequency of IFN--producing cells in M. tuberculosis-stimulated PBMC from nine healthy tuberculin reactors
was found to be 16-fold higher than that in six tuberculin-negative
persons (P = 0.004). This suggests that the assay
primarily detects production of IFN- by previously sensitized T
cells. The frequency of IFN--producing cells was highest in healthy
tuberculin reactors (median, 294/105), intermediate in
patients with moderately advanced tuberculosis (median,
126/105), and lowest in patients with far advanced
tuberculosis (median, 18/105), and this linear trend was
statistically significant (Fig. 1A) (P < 0.05). Two of nine patients with moderately
advanced tuberculosis had a high frequency of IFN--producing cells,
but they were clinically indistinguishable from the other seven
patients.
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FIG. 1.
Frequency of IFN--producing cells in stimulated PBMC.
PBMC were obtained from six healthy tuberculin-negative persons
(PPD ), nine healthy tuberculin reactors (PPD+), nine patients with
moderately advanced tuberculosis (MA), and six patients with far
advanced tuberculosis (FA). The frequency of IFN--producing cells
upon stimulation with M. tuberculosis (A) or PHA (B) was
determined by ELISPOT. Each circle represents the number of
IFN--producing cells per 105 cells for one person. The
horizontal bars indicate median values.
|
|
PHA-stimulated PBMC from all four groups had similar frequencies of
IFN--producing cells (Fig. 1B) (P = 0.22),
demonstrating that the reduced frequency of M. tuberculosis-stimulated cytokine-producing cells from healthy
tuberculin-negative persons and tuberculosis patients was
antigen-specific and was not due to a generalized inability to produce
IFN-.
We measured IFN- concentrations in supernatants of M. tuberculosis-stimulated PBMC and found that IFN- concentrations
closely paralleled the frequency of IFN--producing cells
(correlation coefficient = 0.86), confirming prior studies showing
that IFN- production varies inversely with the severity of disease
due to M. tuberculosis (5, 15).
Frequency of IFN--producing CD8+ and
CD4+ cells in M. tuberculosis-stimulated
PBMC.
CD4+ cells are considered the major source of
IFN- produced in response to microbial pathogens. However, there is
increasing evidence that CD8+ T cells contribute to
immunity against tuberculosis in animals (12, 16, 21) and
in humans (8, 9, 17, 18). To measure the frequency of
IFN--producing CD8+ cells, PBMC were cultured with
heat-killed M. tuberculosis for 72 h, at which point
CD8+ T cells were positively selected (>95%
CD8+) and incubated in ELISPOT plates. The frequency of
IFN--producing CD8+ T cells in the four groups
paralleled findings for PBMC, falling with increasing disease severity
(P < 0.03) (Fig. 2A).
Because live mycobacteria activate CD8+ cells more
effectively than dead organisms (23), we may have underestimated the frequency of IFN--producing CD8+
cells.
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FIG. 2.
Frequency of IFN--producing CD8+ cells
(A) and CD4+ cells (B) in M. tuberculosis-stimulated PBMC. PBMC were obtained from six healthy
tuberculin-negative persons (PPD), nine healthy tuberculin reactors
(PPD+), nine patients with moderately advanced tuberculosis (MA), and
six patients with far advanced tuberculosis (FA). The frequency of
IFN--producing cells after stimulation with M. tuberculosis was determined by ELISPOT. Each circle represents the
number of IFN--producing cells per 105 CD8+
or CD4+ cells for one person. The horizontal bars indicate
median values.
|
|
To compare the frequencies of IFN--producing CD4+ and
CD8+ cells, the ELISPOT assay was applied to positively
selected CD4+ cells isolated from M. tuberculosis-stimulated PBMC (Fig. 2B). The results paralleled
those found for CD8+ cells. The numbers of
IFN--producing cells per 105 CD4+ and
CD8+ T cells were similar in healthy tuberculin reactors
(medians of 195 and 124, respectively) and in patients with moderately advanced tuberculosis (medians of 40 and 63, respectively).
IFN- production per cell.
To evaluate IFN- production
per cell, we used an integrated image analysis system (4)
to quantify the density of each spot in the ELISPOT plate. A spot
density of zero was assigned to two patients with far advanced
tuberculosis, for whom no spots were present. The median spot density
of CD8+ cells was highest in healthy tuberculin reactors,
intermediate in patients with moderately advanced tuberculosis, and
lowest in patients with far advanced tuberculosis (test for linear
trend, P = 0.003) (Fig.
3A). Similar findings were observed for
CD4+ cells (P < 0.0001, Fig. 3B).
Comparing the values in Fig. 3A with those in Fig. 3B, the spot
densities of CD4+ and CD8+ cells were found to
be similar in all three groups, indicating that the amounts of IFN-
produced per cell were similar for CD4+ and
CD8+ cells.
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FIG. 3.
IFN- production per CD8+ cell (A) and
CD4+ cell (B). IFN- production per cell was estimated by
measuring the density of spots on the ELISPOT plates for healthy
tuberculin reactors and tuberculosis patients shown in Fig. 2, using an
integrated image analysis system. The y axis shows spot
density in arbitrary units. Each circle represents the mean spot
density for one person. The horizontal bars indicate median values.
|
|
Effects of depleting CD8+ or CD4+ T cells
on IFN- production.
Our data above demonstrate that both
CD8+ and CD4+ T cells contribute to IFN-
production by M. tuberculosis-stimulated PBMC. To determine
if CD8+ or CD4+ cells were required for the
reciprocal subpopulation to produce IFN-, we depleted PBMC from
three healthy tuberculin reactors of either CD8+ or
CD4+ cells prior to culture with M. tuberculosis
and measured the frequency of IFN--producing cells after 72 h.
CD4+ cells comprised 48% ± 7% (mean ± standard
error) of PBMC, 71% ± 7% of CD8-depleted PBMC, and 0.2% ± 0.1% of
CD4-depleted PBMC. CD8+ cells comprised 29% ± 2% of
PBMC, 0.8% ± 0.6% of CD8-depleted PBMC, and 58% ± 6% of
CD4-depleted PBMC.
Depletion of CD8+ cells modestly reduced the frequency of
IFN--producing cells (Fig. 4A),
presumably because of the removal of CD8+ cells and an
increased number of cells that do not produce IFN-, such as B cells.
In contrast, depletion of CD4+ cells completely eliminated
IFN--producing cells. These results were confirmed by measurement of
IFN- levels in supernatants (Fig. 4B). Depletion of CD4+
cells may have abolished IFN- production by eliminating
CD4+ monocytes and reducing the number of
antigen-presenting cells. However, the percentages of CD4+
cells were similar in CD8-depleted and CD4-depleted PBMC (4.4 and
3.4%, respectively). These findings demonstrate that CD4+
cells are required for CD8+ cells to produce IFN- in
response to M. tuberculosis.
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FIG. 4.
Effect of depletion of CD8+ or
CD4+ cells on IFN- production. PBMC, CD8-depleted PBMC,
and CD4-depleted PBMC from three healthy tuberculin reactors were
cultured with M. tuberculosis for 72 h. The frequency
of IFN--producing cells per 105 cells was determined by
ELISPOT (A), and IFN- concentrations in supernatants were measured
by enzyme-linked immunosorbent assay (B). Mean values and standard
errors are shown.
|
|
Conclusions.
In this study, we found that the proportions of
PBMC and CD4+ and CD8+ cells that produce
IFN- in response to M. tuberculosis were reduced in
patients with tuberculosis, particularly in those with far advanced
disease. IFN- production per CD4+ or CD8+
cell was also reduced in tuberculosis patients. These results indicate
that IFN- production by CD8+ and CD4+ cells
correlates with the clinical manifestations of M. tuberculosis infection in humans. The proportions of cells
producing IFN- and the amounts of IFN- produced per cell were
similar for CD8+ and CD4+ cells, suggesting
that they both contribute significantly to IFN- production. However,
depletion of CD4+ but not CD8+ cells prior to
stimulation of PBMC with M. tuberculosis completely abolished IFN- production, demonstrating that CD4+ cells
are required for CD8+ cells to produce IFN-.
Many investigators have found that M. tuberculosis-induced
IFN- production by T cells is reduced in tuberculosis patients compared to healthy tuberculin reactors (6, 11, 22, 26), and one study demonstrated that the percentage of M. tuberculosis-stimulated CD4+IFN-+ cells
is decreased in tuberculosis patients (3). Our present report confirms and extends these observations. First, we found that
M. tuberculosis-induced IFN- production paralleled the
percentages of CD4+ and CD8+ cells that produce
IFN-. In addition, we found reduced production of IFN- per
CD4+ and CD8+ cell in tuberculosis patients,
compared to healthy tuberculin reactors. Our findings differ from those
of Surcel and colleagues, who reported that the frequency of
IFN--producing cells in M. tuberculosis-stimulated PBMC
of tuberculosis patients was higher than that in healthy tuberculin
reactors (19). Two factors may explain this difference.
First, Surcel et al. studied a heterogeneous group of patients with
pulmonary and extrapulmonary tuberculosis, whereas we evaluated a more
homogeneous population of patients with pulmonary disease. Second, our
ELISPOT assay may be more sensitive, as the mean frequency of
IFN--producing cells was approximately 10-fold higher in the present
study than in the report of Surcel et al.
Although CD4+ T cells clearly play a central role in
immunity to M. tuberculosis, a growing body of evidence
indicates that CD8+ cells also contribute to immune
defenses against this pathogen. In murine models, elimination of
CD8+ T cells by gene deletion greatly increases
susceptibility to tuberculosis (16). CD8+
cells can combat mycobacterial infection by lysing infected cells (13) or by producing IFN- (12, 21) or
molecules with antimicrobial activity (17, 18). In humans,
M. tuberculosis-specific CD8+ cytolytic T cells
have been isolated from bronchoalveolar lavage fluid, suggesting that
they contribute to immune responses in the lung (20). In
addition, CD8+ cells that produce IFN- and exhibit
cytolytic activity are present in the blood of healthy tuberculin
reactors and of persons vaccinated with bacillus Calmette-Guérin
(8, 9, 14, 24). However, the relative contributions of
CD4+ and CD8+ T cells to IFN- production in
humans have not been previously evaluated. Our present results show
that a similar proportion of CD4+ and CD8+
cells produce IFN- in response to M. tuberculosis and
that CD4+ and CD8+ cells produce comparable
amounts of IFN- per cell, suggesting that CD8+ cells
contribute significantly to IFN- production in persons infected with
M. tuberculosis.
Although CD8+ and CD4+ cells were similar in
their capacities to produce IFN-, depletion of CD4+
cells from PBMC prior to stimulation with M. tuberculosis
completely abolished IFN- production by CD8+ and other
cells, whereas depletion of CD8+ cells did not have this
effect. This suggests that CD4+ cells are essential for
CD8+ cells to produce IFN- in response to M. tuberculosis. In many experimental systems, CD4+ T
cells are required for induction of CD8+ T-cell responses
and maintenance of long-term CD8+ memory T cells. This
effect may be mediated through CD40-dependent or CD40-independent
mechanisms, including interleukin-2 production by CD4+
cells (1, 2, 7). Studies are currently under way in our
laboratory to evaluate this interaction between CD4+ and
CD8+ T cells.
| |
ACKNOWLEDGMENTS |
This study was supported by the National Institutes of Health
(A127285), the Center for Pulmonary and Infectious Disease Control, and
the Cain Foundation for Infectious Disease Research. Peter F. Barnes
holds the Margaret E. Byers Cain Chair for Tuberculosis Research.
M. tuberculosis Erdman was provided through contract AI05074
from the National Institute of Allergy and Infectious Diseases.
We thank Patrick Brennan for provision of heat-killed M. tuberculosis Erdman.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: CPIDC,
University of Texas Health Center, 11937 U.S. Hwy. 271, Tyler, TX
75708-3154. Phone: (903) 877-7790. Fax: (903) 877-5516. E-mail:
Peter.Barnes{at}uthct.edu.
Editor:
S. H. E. Kaufmann
| |
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Infection and Immunity, May 2001, p. 3497-3501, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3497-3501.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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