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Infect Immun, February 1998, p. 830-834, Vol. 66, No. 2
National Institute for Medical Research,
London NW7 1AA, United Kingdom
Received 7 July 1997/Returned for modification 22 August
1997/Accepted 29 October 1997
The role of CD8 T cells in controlling Mycobacterium
tuberculosis infections in mice was confirmed by comparing the
levels of growth of the organism in control, major histocompatibility complex class II knockout, and athymic mice and by transferring T-cell
populations into athymic mice. By using donor mice which were incapable
of making gamma interferon (IFN- Cell-mediated immunity is crucial
for the control of mycobacterial infections. Athymic mice
(4) and mice whose T cells have been depleted (22,
23) are much more susceptible to infection with mycobacteria than
euthymic or unmanipulated mice. However, the contributions of the
different components of the T-cell response are unclear. CD4 T cells
are thought to play a major role in controlling infections with the
primary human tubercle bacillus, Mycobacterium tuberculosis;
individuals with reduced CD4 counts, from infection with human
immunodeficiency virus, for example, are known to be more susceptible
to M. tuberculosis infections (12). Activation of
CD4 cells by antigen in association with major histocompatibility complex (MHC) class II molecules results in clonal expansion and the
production of cytokines, most notably gamma interferon (IFN- CD8 T cells are known to contribute to the protective response against
M. tuberculosis, but the mechanism(s) by which they exert
this protective effect is unknown. CD8 T cells produce a range of
cytokines, including IFN- In this study, we have used MHC class II-deficient mice and athymic
mice to confirm the role of non-CD4 T-cell-mediated mechanisms in
protection against M. tuberculosis infection. Using transfer of purified CD4 and CD8 cells into athymic mice, we have demonstrated that these cells contribute equally to protective immunity in this
system. However, by using mice with deletions of the IFN- In preliminary experiments, the levels of growth of M. tuberculosis in MHC class II knockout, athymic, and normal mice
were compared. MHC class II knockout (A
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Protection against Mycobacterium tuberculosis
Infection by CD8+ T Cells Requires the Production of
Gamma Interferon
and
ABSTRACT
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Abstract
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References
), it was shown that IFN-
production was essential for CD8 cell mediation of protective immunity
against M. tuberculosis.
TEXT
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Abstract
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References
), which
activate macrophages so that they become mycobactericidal. Mice with
deletions of the IFN- gene are much more susceptible to M. tuberculosis infection than wild-type mice (5, 9). However, in addition to CD4 cells, other components of the
cell-mediated response are thought to play roles in controlling
infection with M. tuberculosis. For example, CD8 T cells
have been shown to be involved (20, 24): 
2
microglobulin-deficient knockout mice, which lack an effective CD8
response, show increased susceptibility to M. tuberculosis
infection (10). Other cell types, such as T cells bearing
the /
T-cell receptor (19) and NK cells
(1), are also thought to have roles in protection against
intracellular bacteria, while a number of T cells with novel phenotypes
and unknown functions have been shown to recognize mycobacterial
antigens (2, 28).
(11, 17, 25, 26), but their
primary role is thought to be cytotoxic. However, it has recently been
shown that mice with a targeted disruption in either the perforin gene
or the granzyme gene and mice which are Fas receptor defective are no
more susceptible to infection with M. tuberculosis than are
wild-type mice (6, 16). Since perforin (13, 18)
and Fas-Fas ligand interactions (21, 27, 31) are thought to
be the primary mechanisms of cytotoxicity mediated by CD8 T cells, such
cells may contribute their antimycobacterial activity through
noncytotoxic pathways.
gene as
T-cell donors, we have shown that production of IFN- is required in
order for CD8 T cells to exert their antimycobacterial effect.
/) mice were
obtained as a breeding nucleus (kindly provided by D. Gray, Hammersmith
Hospital, London, United Kingdom, with permission from D. Mathis,
Institut National de la Santé et de la Recherche Médicale).
These mice were bred from heterozygous (A+/) parents
and genotyped as described previously (7). Heterozygous littermates were used as controls. Stock cultures of M. tuberculosis H37Rv were grown in Dubos 7H9 broth for
14 days, and then they were aliquoted and stored in liquid nitrogen.
For infection, aliquots were thawed, diluted in phosphate-buffered
saline, and inoculated intraperitoneally into mice. The infection was
monitored by removing the lungs and spleens of infected mice at various
intervals; the baseline level of infection of each tissue was estimated
by harvesting organs from the mice 18 h after infection and
determining viable counts. The tissues were weighed and homogenized by
shaking with 2-mm-diameter glass beads in chilled saline with a
Mini-Bead Beater (Biospec Products, Bartlesville, Okla.), and 10-fold
dilutions of the suspension were plated onto Dubos 7H11 agar with Dubos oleic albumic complex supplement (Difco Laboratories, Surrey, United
Kingdom). Numbers of CFU were determined after the plates had been
incubated at 37°C for approximately 20 days. The results are shown in
Fig. 1A and B. In control mice, there was
a transient increase in bacterial counts in the spleen, followed by a
steady decline over 60 days and then by a levelling out of the
infection at approximately 104 CFU per g of tissue. In MHC
class II knockout mice, there was an initial growth of the infection
over the first 60 days, followed by a plateau phase during which the
infection appeared to be controlled but was significantly more severe
than in wild-type mice (Fig. 1A). In lung tissue (Fig. 1B), a similar
pattern emerged, except that in the MHC class II knockout mice, control
of the infection broke down in some of the mice after about 60 days,
when there was a sudden increase in bacterial counts. By day 80, counts
had reached approximately 107 CFU per g of tissue, a
10,000-fold increase over the counts seen in wild-type mice.
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FIG. 1.
Growth of M. tuberculosis in the tissues of
MHC class II knockout, control, and athymic mice. (A and B) Growth in
spleens and lungs, respectively, of MHC class II knockout mice ( 
)
and their wild-type littermates (
). (C and D) Growth in spleens and
lungs, respectively, of MHC class II knockout () and athymic (
)
mice. Data are the geometric means ± the standard errors of the
means for three to five mice. An asterisk indicates a significant
difference between values for MHC class II knockout and control mice
(P < 0.05 by Students' t test). A double
asterisk denotes that at the indicated time, all remaining mice in the
group were killed because of the widely disseminated nature of the
infection.
These results emphasize the importance of the MHC class II-CD4 T-cell pathway in controlling M. tuberculosis infection. However, in spite of the fact that after the first few days of infection there was always a highly significant difference between the level of viable M. tuberculosis organisms in MHC class II knockout mice and the level in control mice, some control of bacterial multiplication did appear to occur in the MHC class II knockout mice. In order to demonstrate that this apparent partial control of the infection in MHC class II knockout mice was mediated by T cells, we compared growth in these mice with growth in athymic mice. Athymic (nude) BALB/c mice were obtained from a breeding colony at the National Institute for Medical Research. Athymic and MHC class II knockout mice were infected intraperitoneally, and the infections were monitored as described above. Whereas the MHC class II knockout mice were again able to control the infection to some degree, growth in athymic mice was unchecked and the mice had to be killed at 40 days because of overwhelming infection (Fig. 1C and D).
These results confirm the importance of CD4 cells in controlling
M. tuberculosis infections but also suggest that a
contribution is made by non-CD4-mediated mechanisms. It has previously
been shown that depletion of CD8 cell populations in mice with anti-CD8 antibodies (20) or abolition of a CD8 response by disruption of the 2 microglobulin gene (10) renders mice highly
susceptible to infection with M. tuberculosis. CD8 T cells
have also been implicated in human tuberculosis; CD8+ T
cells with specificity for mycobacterium-pulsed target cells have been
described (14, 32), and an individual with recurrent tuberculosis was found to have a specific reduction in CD8 T cells (3).
In order to investigate the contribution of CD8 T cells to the control of M. tuberculosis infections in mice, total spleen cells, CD4 T cells, and CD8 T cells were transferred from control BALB/c mice into infected athymic BALB/c mice. Splenocytes were incubated in hypotonic medium to lyse erythrocytes and washed twice. To obtain highly purified populations of CD4 and CD8 cells, cell suspensions were enriched by negative selection with T-cell-subset columns (R & D Systems Inc., Minneapolis, Minn.) according to the manufacturer's instructions. The resulting populations were >90% CD4 or CD8 T cells, as determined by flow cytometric analysis. The cells were washed, resuspended in sterile saline, and injected intravenously such that recipient mice received 5 × 106 cells. The mice were then infected with M. tuberculosis, and organs were harvested 21 days later for CFU counts. The results of a typical experiment are shown in Fig. 2. In athymic mice which had not received any transferred cells, the infection reached approximately 107 CFU per g in the lung (Fig. 2A) and 108 CFU per g in the spleen (Fig. 2B). Transfer of total spleen cells from naive BALB/c mice reduced the number of CFU 100- to 1,000-fold in both tissues. It appeared that CD4 and CD8 T cells contributed approximately equally to the observed protection.
|
The mechanism by which CD8 T cells exert this antimycobacterial
response is not understood. It has been suggested that the cytotoxicity
of mycobacterium-laden target cells could be involved, perhaps through
the release of M. tuberculosis bacilli from ineffective macrophages to cells with greater antimycobacterial potential (15). However, perforin or granzyme knockout mice and Fas
receptor-defective mice, when infected, did not display any increased
susceptibility to infection, compared to wild-type controls (6,
16). Interestingly, both the perforin knockout mice and the Fas
receptor-defective mice had elevated levels of cytokines, including
IFN-, in the absence of infection, and levels in infected mice were
similar to those seen in wild-type mice (16). Thus, neither
perforin-, granzyme-, nor Fas-mediated cytotoxicity appeared to be
involved in the control of these experimental infections (6,
16). Conversely, however, Silva and colleagues (29)
produced CD8+ T-cell clones which were capable of
conferring protection against M. tuberculosis in recipient
mice, and the level of protection correlated with the level of
cytotoxic activity rather than with the level of IFN- secretion.
In a recent study of human cytotoxic cells with mycobacterial
specificity, it was found that CD4 CD8 T
cells lysed macrophages through a Fas-Fas ligand interaction but the
lysis was not associated with mycobacterial killing, whereas CD8+ T-cells lysed macrophages by a Fas-independent pathway
and the lysis resulted in the killing of mycobacteria (30).
The human T-cell lines used for these experiments were unusual in that
they were CD1 restricted.
Since CD8 T cells were clearly able to confer significant levels of
protection against M. tuberculosis in our cell transfer model, we next investigated the role of IFN- in this protection. Again athymic mice were recipients of either total spleen cells or CD8
cells. This time, however, donor mice were either normal BALB/c mice or
IFN- knockout mice (8) and recipient mice received 3 × 106 cells. The results (Fig.
3) clearly demonstrate the requirement for IFN-. Transfer of total spleen cells or CD8 T cells from normal
mice gave protection, although the level of protection was slightly
lower than that seen in the previous experiment (Fig. 2). This was
probably because the number of cells transferred was lower (3 × 106 rather than 5 × 106). However, the
protection seen in both organs was significant (P < 0.05). Importantly, transfer of cells from IFN- knockout mice gave
no protection.
|
VE) BALB/c mice. (A and B) Results for
the lungs and spleen, respectively. The experimental design was
identical to that for Fig. Thus, the results reported in this study confirm the role of CD8 T
cells in the control of M. tuberculosis infections in mice. We have also demonstrated that this control requires the ability of the
CD8 cells to produce IFN-, suggesting that such cells may exert
their effects through classical cytokine-mediated macrophage activation
rather than through a cytotoxic mechanism. The recent demonstration
that human CD1-restricted CD8 T cells were able to kill mycobacteria in
vitro through a cytotoxicity-mediated pathway (30) suggests
that different subpopulations of CD8 cells may have different effector
mechanisms; since no murine equivalent of the CD1-restricted CD8 T cell
has been described, this mechanism may be absent in mice.
Alternatively, the results reported earlier for murine CD8 T-cell lines
(29) or human CD8, CD1-restricted T-cell lines
(30) may reflect the activity of primed or memory T cells,
whereas the results reported in the present study reflect the activity
of unprimed cells. Primed CD8 T cells have been shown to be
hyperreactive to antigenic challenge in vitro and may employ different
effector mechanisms. That production of IFN- by CD8 T cells is
required in order to control infection has also been reported for viral
infections (11, 26), where cytotoxicity has long been
thought to be the major mechanism of CD8-mediated antiviral activity.
IFN- and other cytokines have been shown to be major components of
the mechanism by which hepatitis B virus is controlled in mice by CD8
cells without the killing of hepatocytes (11). The results
reported in this study demonstrate that IFN- is essential for
CD8-mediated protection against M. tuberculosis infection in mice.
| |
FOOTNOTES |
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* Corresponding author. Mailing address: National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Phone: 0181 959 3666, ext. 2354. Fax: 0181 913 8528. E-mail: jcolst.{at}nimr.mrc.ac.uk.
Present address: Ion Transport Unit, National Heart and Lung
Institute, London SW3 6LR, United Kingdom.
Editor: R. E. McCallum
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Infect Immun, February 1998, p. 830-834, Vol. 66, No. 2
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