By
From the * Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and
Harvard Medical School, Boston, Massachusetts 02115; the Department of Immunology and
Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115; and the § Gwen
Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois 60637
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Abstract |
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Cellular immunity against Mycobacterium tuberculosis controls infection in the majority of infected humans. Studies in mice have delineated an important role for CD4+ T cells and cytokines including interferon and tumor necrosis factor
in the response to infection with mycobacteria. Recently, the identification of CD8+ CD1-restricted T cells that kill M. tuberculosis
organisms via granulysin and the rapid death after infection of
2 microglobulin deficient mice
in humans has drawn attention to a critical role for CD8+ T cells. The nature of mycobacterial-specific CD8+ T cells has been an enigma because few have been identified in any species.
Here, we delineate the contribution of class I MHC-restricted T cells in the defense against tuberculosis as transporter associated with antigen processing (TAP)1-deficient mice died rapidly, bore a greater bacterial burden, and had more severe tissue pathology than control mice. In contrast,
CD1D
/
mice were not significantly different in their susceptibility to infection than control
mice. This data demonstrates a critical role for TAP-dependent peptide antigen presentation and
provides further evidence that class I MHC-restricted CD8+ T cells, the major T cell subset
activated by this antigen processing pathway, play an essential role in immunity to tuberculosis.
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Introduction |
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Tuberculosis is the most common cause of death from an infectious pathogen in the world (1). The causative agent, Mycobacterium tuberculosis, infects and grows intracellularly in macrophages, induces an intense immune response, and leads to the development of caseating granulomas, the pathological hallmark of the disease. It is well established that CD4+ T cells are critical in the immune response to M. tuberculosis in rodents and humans. This may be a consequence of the intracellular compartmentalization of M. tuberculosis in the phagolysosome, which could favor entry of its proteins into the class II MHC antigen-processing pathway (2).
The participation of CD8+ T cells in immunity to M. tuberculosis is less clearly defined. Prior studies using antibody
mediated T cell subset depletion (3) and adoptive transfer of
purified T cell subsets (4) were able to show that CD8+
T cells could reduce CFU of M. tuberculosis in the spleen of infected mice, although the effect was consistently weaker
than that observed for CD4+ T cells (3, 4). Infection of mice
with the less virulent Mycobacterium bovis (Bacillus Calmette-Guerin, BCG) consistently found that CD8+ T cells made
no contribution to immunity (7). This difference between
the immune response to M. tuberculosis and M. bovis BCG may be a reflection of their differing virulences. However,
none of these studies examined the immune response in the
lung, the site where rodents fail to control the infection after intravenous infection, nor were any other variables examined, such as pathology or survival. Furthermore, it has
been difficult even to demonstrate the presence of mycobacterial-specific CD8+ T cells in human tuberculosis patients until recently (10, 11). Given the relative lack of data
implicating CD8+ T cells in immunity to M. tuberculosis, it
was a remarkable finding that mice genetically deficient in
2 microglobulin (
2m),1 and as a consequence lacking in
CD8+ T cells, were unable to control infection, particularly in the lung, and succumbed prematurely to tuberculosis (12). Although the susceptible phenotype observed in
2m-deficient mice was thought to be secondary to the
loss of class I MHC-restricted CD8+ T cells,
2m is also a
component of a number of other antigen-presenting molecules, including H2-M3, TL, Qa-1, Qa-2, and CD1d. Because the MHC-encoded class I, H2-M3, Qa-1, and Qa-2
molecules have all been shown to bind peptide antigens
loaded in a transporter-associated with antigen processing
(TAP)-dependent fashion, whereas CD1 molecules, including CD1d, are characterized to bind lipid-based antigens, we sought to discriminate these pathways.
The CD1 family of 2m-associated, non-MHC locus-
encoded proteins are able to present hydrophobic lipids and
glycolipids to T cells. Specifically, the human group 1 CD1
proteins (CD1a, -b, and -c) have been shown to present
mycobacterial antigens such as mycolic acid, glucose monomycolate, and lipoarabinomannan to human
/
-TCR+ T
cells (13). The mouse has a pair of CD1 genes that are
likely to represent a recent duplication, and are homologous to the human group 2 CD1 protein CD1d. Phosphatidylinositol-containing compounds have been eluted
from murine CD1d (16), and both murine and human CD1d
can present the glycolipid
-galactosylphytosphingosine to
T cells in a TAP-independent manner (17, 18). The ability of murine CD1d to bind glycolipids that are structurally
similar to CD1-restricted mycobacterial antigens, together
with the delineation of CD1d-restricted T cells that use a
diverse TCR repertoire (19), led us to hypothesize that
CD1d may also be capable of presenting mycobacterial antigens to murine T cells.
In contrast to the presentation of lipid antigens by CD1,
class I MHC presents peptides to CD8+ T cells. The class I
MHC antigen-processing pathway is dependent upon cleavage and processing of protein antigens (by the proteosome), followed by transport of the peptides from the cytosol into
the endoplasmic reticulum (ER) by the TAP complex. Here,
the processed peptides associate with the class I MHC and
2m proteins to form a trimeric complex (22). The TAP
protein is a heterodimer of the tap1 and tap2 gene products,
and mediates the translocation of peptides from the cytoplasm into the ER. Cells that are deficient in either TAP1
or TAP2 are unable to efficiently process peptides derived
from cytosolic proteins by the class I MHC pathway. In tap1-deficient mice, this defect in the class I MHC antigen-processing pathway results in greatly reduced numbers of
CD8+ T cells in all lymphoid organs, as CD8+ T cells are
not positively selected during T cell maturation in the
thymus (23). In contrast, TAP deficiency is not believed to
lead to a deficiency of CD1-restricted T cells, as all
examples of CD1-restricted antigen recognition by T cells
have been determined to be TAP independent (17, 24, 25).
We therefore felt that the TAP1-deficient (TAP1
/
) and
CD1D-deficient (CD1D
/
) mice would be important independent models to determine the significance of CD8+
T cells in immunity to M. tuberculosis.
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Materials and Methods |
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Mice.
6-8-wk-old male (129/Sv,C57BL/6) TAP1Bacteria and Infections.
Virulent M. tuberculosis (Erdman strain; originally obtained from Barry Bloom, Albert Einstein College of Medicine, Bronx, NY) was passaged through mice and then grown in Middlebrook 7H9 supplemented with oleic acid- albumin-dextrose complex (OADC; Difco), before freezing aliquots atFlow Cytometry.
Venous blood from mice infected with M. tuberculosis was obtained by retro-orbital puncture. 50 µl of blood anti-coagulated with heparin was stained with PE-conjugated anti-CD8 antibody (clone 53-6.72) (PharMingen) or a control antibody. The RBCs were lysed with NH4Cl and after extensive washing with buffer the samples were resuspended in 1% paraformaldehyde-PBS and analyzed after 24 h using a FACSortTM (Becton Dickinson). The percentage of CD8+ T cells within the lymphoid gate was determined.CFU Determination.
To quantify viable mycobacteria in the infected mouse organs, the lungs, liver, and spleen were aseptically removed from each killed animal. The left lung, left lobe of the liver, and half of the spleen were homogenized in 0.02% Tween 80 in normal saline using Teflon homogenizers (Fischer). 10-fold serial dilutions were plated onto 7H10 agar plates and colonies were counted after incubation for 3 wk at 37°C.Histology.
Tissues for histological studies were fixed in 10% buffered formalin and then embedded in paraffin blocks. 5-µm sections were stained with hematoxylin and eosin or by the Fite-Faraco method for acid-fast bacilli (AFB) (29). ![]() |
Results |
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To test the hypothesis that the increased susceptibility of 2m
/
mice to M. tuberculosis was due to the absence of CD1d-restricted T cells, mice that had both the
CD1D1 and CD1D2 genes disrupted by homologous recombination (CD1D
/
mice) were infected with virulent
M. tuberculosis (27). No significant difference between the
mortality of CD1D
/
mice and that of their heterozygous
littermate controls was observed after intravenous infection
with 106 CFU (Fig. 1 A). The median survival time (MST)
was 169 d for the CD1D
/
mice and 136 d for the
CD1D+/
mice. These CD1D
/
mice were used after the
second backcross to C57BL/6 mice, and further studies using CD1D
/
mice after the sixth backcross gave similar
results (data not shown). We also considered whether deletion of CD1D increased the resistance of mice to infection
with M. tuberculosis. Since both C57BL/6 and 129/Sv mice
are relatively resistant to tuberculosis, an increase in resistance of CD1D
/
mice on these genetic backgrounds
would be difficult to detect. Therefore, CD1D
/
mice on
the susceptible BALB/c genetic background were infected. CD1D
/
mice backcrossed eight generations to BALB/c
mice showed no significant differences in survival compared with CD1D+/+ BALB/c mice after infection with M.
tuberculosis (Fig. 1 B). Additional experiments using a higher
(3 × 106) or lower (2 × 105) inoculum did not reveal any
differences in survival (data not shown). Experiments done
in parallel demonstrated a significant reduction in survival
for
2m
/
mice compared with
2m+/+ mice (data not
shown), as had been reported previously (12). These results
indicate that the increased mortality of
2m
/
mice was
not due to an absence of CD1d-restricted T cells.
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As the absence of the CD1D1 and CD1D2 genes
did not significantly alter the survival of mice, TAP1/
mice were infected with M. tuberculosis to independently
verify that the susceptibility of
2m
/
mice to tuberculosis
was secondary to the absence of T cells restricted to MHC
molecules loaded in the ER in a transporter-dependent manner. The vast majority of such T cells are class I MHC-
restricted CD8+ T cells, and mice with disruption of the
TAP1 gene are known to have a profound deficiency in
CD8+ T cells (26). We confirmed the loss of CD8+ T cells
from peripheral blood after intravenous infection with M. tuberculosis. We found that in infected TAP1+/+ mice,
9.0 ± 0.7% (mean ± SEM) of PBLs were CD8+, whereas
only 1.2 ± 0.1% of PBLs were CD8+ in TAP1
/
mice
(Fig. 2). These results were similar in uninfected TAP1
/
and control mice (30).
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In three separate experiments, a total of 42 TAP1/
mice and 42 control mice were infected intravenously with
106 CFU of M. tuberculosis. It is striking that the TAP1
/
mice were more vulnerable to death from infection than
were control mice (P < 0.0001 by the log-rank test) (Fig.
3). The TAP1
/
mice had a MST of 63 d, and with the
exception of one mouse all were dead by day 91 (Fig. 2). In
contrast, the MST for the control mice was >150 d (Fig.
3). The difference between the survival of the TAP1
/
and the TAP1+/+ mice was highly statistically significant,
and the P values for the individual experiments were P < 0.0001, P = 0.0047, and P < 0.0001. These results demonstrate the importance of an intact TAP-dependent peptide loading antigen presentation pathway for immunity to
tuberculosis and strongly supports a critical role for class I
MHC-restricted CD8+ T cells in the immune response to
M. tuberculosis.
|
To exclude the possibility of a subtle
CD1d-dependent effect that was obscured in the presence
of CD8+ T cells, the survival of TAP1/
CD1D
/
mice
was compared with TAP1
/
CD1D+/+ mice, on a mixed
129/Sv and C57BL/6 genetic background. No significant difference was observed in the survival of these strains of
mice (Fig. 4). The MST was 79 d for the TAP1
/
CD1D
/
mice and 65 d for the TAP1
/
CD1D+/+ mice, which was
similar to other experiments in which TAP1
/
CD1D+/+
mice were infected (Fig. 3). This experiment is consistent
with the conclusion that CD1d does not contribute to a
protective immune response after intravenous inoculation
with M. tuberculosis.
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The
TAP1/
mice were unable to control the progression of
the infection. The number of bacteria deposited in the
spleen, liver, and lungs was determined 1 d after infection
and was comparable to the numbers reported by other investigators (Fig. 5, reference 12). The ability of the mice to
limit the mycobacterial growth was studied at several time
points after infection. In all three organs examined, the
TAP1
/
mice were not able to control the infection as efficiently as the control mice (Fig. 5). For example, the
TAP1
/
mice had a 10-100-fold increase in the number
of mycobacteria isolated from the lung 10 wk after infection. Similar differences were seen in the spleen and liver.
In contrast, the early phase of the infection (days 1-21) was
similar in TAP1
/
and TAP1+/+ mice (Fig. 5 and data not
shown). This result is consistent with the finding that protective CD4+ T cells are present by day 10 after infection,
whereas protective CD8+ T cells do not become apparent
until 3-4 wk after infection (4). These data indicate that the
absence of TAP1 affected the adaptive immune response.
We observed some variability between experiments, particularly in the colony count data. We believe that this variability arose from the use of two different batches of M. tuberculosis. One of the batches was more virulent than the
other. Formalin fixed sections of lung, spleen, and liver,
were stained for mycobacteria (AFB) to confirm the increased bacterial burden in the TAP1
/
mice. In all tissues, but most dramatically in the lung, AFB were more
abundant in tissue obtained from TAP1
/
mice compared
with TAP1+/+ mice (Fig. 6, A and E). Although enumeration of AFB was not done, the tissues from the TAP1
/
mice had more numerous foci containing AFB, and those
foci contained greater numbers of bacilli compared with
tissue taken from TAP1+/+ mice. This is consistent with the
colony count data, and suggests that TAP1
/
mice are defective in their capacity to control infectious foci.
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The TAP1/
mice
had a much greater degree of hepatosplenomegaly and enlargement of the lungs compared with the control mice (data not shown). Lung tissue examined 1 d after infection
appears normal by light microscopy and similar in both the
TAP1+/+ and TAP1
/
mice (Fig. 6, B and F). 1 mo after
infection, the lungs of the TAP1+/+ mice contain abundant
foci of infection containing mixed inflammatory cells and
most major blood vessels were surrounded by inflammatory cells; however, the airspaces of the lungs were well preserved (Fig. 6 C). In contrast, the TAP1
/
mice had severe pneumonia characterized by massive inflammatory cell
infiltrates, and severe reductions in airspace (Fig. 6 G). The
inflammatory cells were chiefly mononuclear cells, with
some areas of granulomatous inflammation where the predominant cell types were epithelioid cells and foamy macrophages. By wk 7, well defined granulomas were observed
grossly. Microscopically, the lungs of the TAP1+/+ mice also
had severe granulomatous pneumonia with reduction of lung aeration (Fig. 6 D). In the TAP1
/
lungs, there was
nearly complete obliteration of the airspace by pneumonia
with spread via the large airways; neutrophilic infiltrates and early signs of tissue necrosis were apparent (Fig. 6 H).
Although there were similar qualitative changes in the nature of the inflammatory infiltrate in the TAP1
/
mice
compared with the control mice, the amount of cellular infiltrate was greater in the TAP1
/
mice at every time point.
In contrast, the infiltrate observed in the TAP1+/+ mice was
more focal and was distributed primarily in a perivascular location with better preservation of the alveolar air space
(Fig. 6 D).
A similar pattern was seen with the spleens and livers.
The spleens of the TAP1/
animals were more disrupted,
and the spleens of both the TAP1
/
and control mice had
numerous giant cells. The livers of both types of mice had
well-defined granulomata, with a tendency for the granulomas in the TAP1
/
mice to be slightly more cellular.
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Discussion |
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Although it is clear that CD8+ T cells play a critical role
in host defense against viral infections and some intracellular infections such as Toxoplasma gondii and Listeria monocytogenes, the role of CD8+ T cells in immunity to tuberculosis remains controversial despite numerous studies that have
examined this question. The 1992 study by Flynn et al. redressed the role of CD8+ T cells in M. tuberculosis infection
using mice deficient in 2m (12). Since
2m forms a heterodimer with the class I MHC heavy chain, mice deficient
in
2m lack surface expression of class I MHC molecules,
and therefore are unable to positively select CD8+ T cells
during thymic T cell development. As a result such mice are largely deficient in CD8+ T cells. When
2m
/
mice
were infected with the Erdman strain of M. tuberculosis, they quickly succumbed to infection. Associated with the
decreased survival time was an increased mycobacterial
burden in the lungs and more severe tissue pathology compared with infected
2m+/+ mice (12).
One interpretation of the increased vulnerability of the
2m
/
mice to M. tuberculosis is that class I MHC-restricted
CD8+ T cells are critical in immunity to tuberculosis.
However, alternative explanations exist. The
2m molecule forms heterodimers with molecules other than the
class I MHC heavy chain, such as class Ib MHC heavy chains (i.e., H2-M3) and the non-MHC-encoded CD1
heavy chain, both of which are antigen-presenting molecules
that present unique bacterial antigens to T cells. H2-M3 is
known to specifically present N-formylated peptides derived from bacterial proteins to murine CD8+ T cells (31).
CD1 is known to present antigens from M. tuberculosis and
Hemophilus influenzae to human CD8+ and CD4
8
T
cells. For example, human CD1b and CD1c present lipid
and glycolipid antigens that are unique to mycobacterial
species, including mycolic acid and lipoarabinomannan to
human T cells, and antigen-specific CD1-restricted human
T cells are able to lyse infected cells and kill the intracellular
mycobacteria (13, 15, 32, 33). Thus, although the
2m
/
experiments strongly implicated a crucial role for class I
MHC-restricted CD8+ T cells in immunity to M. tuberculosis, it is now clear that the effect of deleting
2m also
might be mediated by T cell subsets other than class I
MHC-restricted CD8+ T cells. One strategy to clarify the
role of
2m-dependent T cells in immunity to tuberculosis
was to examine the susceptibility of TAP1
/
or CD1D
/
mice to infection with M. tuberculosis. TAP1
/
mice are
largely deficient in class I MHC-restricted T cells; however, because the recognition of CD1-restricted antigens is TAP independent, the CD1-restricted T cell populations
should be largely unaffected (34, 35). Conversely, CD1D
/
mice have intact CD8+ T cell populations.
The finding that the absence of CD1d did not affect the outcome of M. tuberculosis infection in mice does not exclude the possibility that the human CD1 proteins play an important role in immunity to tuberculosis. Presentation of microbial antigens to T cells has been elucidated for the human group I CD1 proteins (i.e., CD1a, CD1b, and CD1c), but not for CD1d, which may have a greater role in immunoregulation (36). Furthermore, although humans are inherently more susceptible to tuberculosis than are mice, 95% of infected individuals develop long-lived immunity. If the group I CD1 proteins were to participate in the human immune response to M. tuberculosis, evolutionary selection may explain why group I CD1 genes are preserved in the human but not the murine genome. In this regard, it is of great interest that guinea pigs, another species that is highly susceptible to tuberculosis, has also retained the group I CD1 genes (Dascher, C.C., manuscript in preparation). The guinea pig may be a more suitable experimental animal for investigating the role of the group I CD1 proteins in the immune response to M. tuberculosis.
We found that TAP1/
mice had an increased susceptibility to tuberculosis that was manifested by a decreased
survival after intravenous infection, increased mycobacterial
burden in the lungs, liver, and spleen, and overall more severe pathological changes in the target organs. These data
establish that antigen-processing pathways that require TAP-dependent peptide loading are critical in the development
and maintenance of protective immunity to virulent M. tuberculosis. In considering the
2m-associated antigen-presenting molecules, CD1 and TL are TAP independent (24, 37, 38). Presentation of antigens by H2-M3 and Qa-1 can be either
TAP dependent or independent (35, 35, 37, 39). There exist
examples of antigen presentation during intracellular infection with Listeria monocytogenes that are TAP independent for
H2-M3 (39) and TAP dependent for Qa-1 (40). Qa-2 is
TAP dependent (41), and although Qa-2 can bind peptides,
T cell recognition of Qa-2 has not been demonstrated.
Therefore, the TAP-dependent antigen-processing pathway
primarily activates class I MHC-restricted CD8+ T cells.
CD8+ class I MHC-restricted T cells are not the only
cellular subset that is abnormal in the TAP1/
mice. Although their numbers and capacity to kill the YAC-1 cell line are normal, the repertoire of NK cells may be altered
secondary to a change in the peptides bound by the class I
MHC molecules and the overall decreased surface expression of class I MHC (30). Likewise, there is a relative expansion of NK1+ T cells in TAP1
/
mice (42), although
these cells, which require CD1d1 for their positive selection, do not appear to be critical for the long-term survival
of mice infected under the conditions used in this study.
Further work will be needed to clarify the role of CD8+
T cells during M. tuberculosis infection. It appears that progression of M. tuberculosis infection in both perforin- and
fas-deficient mice is unaltered, and suggests that the cytolytic function of CD8+ T cells is not critical in immunity to
tuberculosis (43, 44). Other work suggests that the crucial
function of CD8+ T cells is mediated by IFN- (45). We
have found that 40-60% of the CD4+ T cells in the lungs of
infected mice are primed to produce IFN-
(Chackerian,
A., and S.M. Behar, manuscript in preparation), and it remains to be determined whether CD8+ T cells serve a role
other than the production of IFN-
. For example, CD8+
CTLs and NK cells produce granulysin, a protein found
in cytotoxic granules that has direct microbicidal action
against a variety of microorganisms (33). Granulysin does
not have activity against intracellular bacteria unless it can
gain access via a pore-forming molecule such as perforin
(33). Although perforin-deficient mice are initially able to
control mycobacterial infections (43), perforin and granulysin may have a role late in infection, for example in preventing recrudescence of disease.
Immunity to intracellular bacterial infections has been shown to be a cooperative effort between the innate and adaptive immune responses. Optimum protection against M. tuberculosis, L. monocytogenes, and Listeria major requires synergism between CD4+ and CD8+ T cells. Although the unique roles of each T cell subset during the course of infection remain to be elucidated, an understanding of these roles is critical to the rational development of vaccines and immunotherapeutic strategies.
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Footnotes |
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Address correspondence to Samuel M. Behar, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith Bldg., Rm. 516C, 1 Jimmy Fund Way, Boston, MA 02115. Phone: 617-525-1033; Fax: 617-525-1010; E-mail: sbehar{at}rics.bwh.harvard.edu
Received for publication 8 April 1999.
The authors thank Chris Roy for his excellent technical assistance; Steve Jean, Linda Callahan, and the staff of the Animal Biohazard Containment Suite at the Dana-Farber Cancer Institute for their help in facilitating these experiments; and Frank Borriello for helpful discussions.
This work was supported by National Institutes of Health grants AR39582 (to M.B. Brenner), AR01978 (to S.M. Behar), AI43407 (to C.-R. Wang), and AI40171, as well as a gift from the Mathers Foundation to M.J. Grusby. M.J. Grusby is a Scholar of the Leukemia Society of America.
Abbreviations used in this paper
AFB, acid fast bacilli;
2m,
2 microglobulin;
ER, endoplasmic reticulum;
MST, mean survival time;
TAP, transporter associated with antigen processing.
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