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Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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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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CD8 T cells deploy multiple effector functions including lysis of
target cells and production of cytokines such as IFN-
and TNF
(3, 7). CTL induce target cell lysis through Fas/Fas
ligand interactions or a perforin-dependent mechanism.
Perforin-mediated cytolysis is the major pathway involved in lysis of
tumor or target cells infected by intracellular pathogens (8, 9). CTL recognition of a target cell causes release of perforin
and granzymes from intracellular stores, resulting in pore formation
and apoptosis of the target cell. CTL also produce cytokines and
chemokines that recruit phagocytic cells to the site of infection.
Lysis of infected cells presumably results in release of intracellular
bacteria, which are subsequently killed by phagocytes. Studies
examining protective immunity to Lm infection in the mouse model have
revealed both perforin-dependent (10) and -independent CD8
T cell mechanisms (11, 12). CD8 T cells lacking IFN- or
TNF have also been shown to provide high levels of anti-Lm immunity
(13, 14). Thus, while it is clear that CTL are critical
for protective immunity, a single effector function of CD8 T cells
indispensable for protection against Lm has not been identified,
suggesting that the immune system evolved overlapping effector
functions to counteract multifactoral virulence strategies of microbes.
The roles of the various immune effector functions may only be resolved
by examining specific interactions between host immune effectors and
microbial virulence factors through genetic manipulation not only of
the host, but also of the pathogen.
The critical role of CD8 T cells in protective immunity against Lm is believed to relate to the cytosolic niche of Lm. Cytosolic growth allows evasion of many aspects of immune surveillance but results in recognition by Ag-specific CTL that lyse infected cells and terminate intracellular bacterial replication. CTL play a much less important role in the control of pathogens such as Salmonella and Mycobacterium that grow in the endosomal compartment, supporting the notion that the importance of CD8 T cells in Lm control relates to the cytoplasmic niche of this bacterium. However, Lm replicates rapidly within host cells resulting in spontaneous host cell lysis within hours after infection. This raises doubts about the importance of CTL-dependent release of intracellular bacteria. Furthermore, the cytolytic effector function of CD8 T cells is not required for protective immunity against intracellular pathogens such as vesicular stomatitis virus (VSV) (15) and Trypanosoma cruzi (16), among others, that also find their replicative niche in the host cell cytosol. This line of evidence suggests that the importance of CD8 T cells may relate to other aspects of Lm infection that are not shared by all intracytoplasmic pathogens.
We hypothesize that CTL lysis of infected target cells is critical for protective immunity against Lm not only because this bacterium grows in the host cell cytosol but more importantly because it spreads directly from cell to cell. Intercellular actin-based motility allows rapid bacterial dissemination and CTL lysis of infected cells may prevent or minimize Lm spread to uninfected cells (17). A prediction based on this hypothesis is that the clearance of bacteria unable to spread directly from cell to cell will be less dependent on CTL, particularly on the lytic function of CTL. In this study, we test this prediction by assessing the extent to which perforin-mediated cytolysis contributes to CD8 T cell-mediated immunity against a recombinant Lm (rLm) strain defective in cell-cell spread.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6) and perforin-deficient B6 (PKO) (18)
mice from National Cancer Institute (Frederick, MD) and The Jackson
Laboratory (Bar Harbor, ME), respectively, were maintained in
Institutional Animal Care and Use Committee-approved facilities. rLm
strains in wild-type 10403S background (wt rLm)-gp and rLm in
cell spread-deficient background (
actA rLm)-gp secreting
CTL epitope gp33–41 from lymphocytic choriomeningitis virus (LCMV)
were constructed as described (19) on the wild-type strain
10403S and actA backgrounds, respectively. The
actA strain was derived from 10403S by an inframe
deletion of the actA sequence encoding aa 20–330. Two pairs
of isogenic wt rLm-gp and actA rLm-gp strains were used:
one erythromycin (Em)-resistant pair with gp33–41 embedded in a
dihydrofolate reductase fusion, and one kanamycin (Km)-resistant pair
with gp33–41 in an alkaline phosphatase fusion (20).
Similar results were obtained with the two pairs of strains, providing
cross-validation of results and demonstrating that the gp33–41 epitope
context did not impact in vivo growth in naive mice and clearance rates
in immune mice (data not shown). Recombinant murine hepatitis virus
(MHV) strain SA59REGFP
(MHV-gfp) expressing enhanced green fluorescent protein (EGFP) was
derived from strain MHV-A59 by targeted recombination of the EGFP gene
into the gene 4 sequence. The derivative MHV-gfp-gp expresses an
EGFP-gp33–41 fusion. MHV and LCMV viruses were propagated as described
(20, 21).
Animal experiments
Viral immunizations of mice were done i.p. with 6
log10 PFU MHV or 5.3 log10
PFU LCMV Armstrong. Hepatic MHV titers were determined by plaque assay
as described (21). Mice were challenged i.v. >21 days
after viral immunization with 6 log10 CFU wt
rLm-gp or 7.7 log10 CFU actA
rLm-gp. CFU rLm in the spleen was determined for days 2 or 3
postchallenge as described (20). Mixed infections involved
the Em-resistant wt rLm-gp strain and the Km-resistant
actA rLm-gp strain, each given at the same dose as in
individual infections, and spleen homogenates were plated on media with
Em or Km.
Flow cytometry
Splenocytes were stained with anti-CD8, anti-CD43 mAb
(BD PharMingen, San Diego, CA) and Dbgp33
tetramers. Intracellular IFN- staining was performed with the
Cytofix/Cytoperm Plus kit (BD PharMingen) after 5 h of in vitro
stimulations with or without 1 µM synthetic gp33–41 (KAVYNFATM)
peptide.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We hypothesized that CTL cytolysis plays a critical role in
control of secondary listeriosis by limiting direct cell-cell spread of
Lm. As a first step toward testing this hypothesis, we determined
whether Ag-specific memory CTL enhance clearance of rLm strains capable
of or defective in cell-cell spread. We used a previously described
system designed to examine the role of Ag-specific memory CTL in
protective immunity to Lm (19, 20). B6 mice were immunized
with LCMV to establish LCMV-specific memory CTL. Immunized and naive
control mice were then challenged with either a cell spread-capable or
a cell spread-defective rLm strain secreting the gp33–41 epitope of
LCMV (wt rLm-gp or actA rLm-gp, respectively). In this
system, protective immunity against the rLm strains is strictly
dependent on a pool of recalled CTL specific to the gp33–41
epitope.
To assess the efficacy of Ag-specific memory cells to control infection
with rLm capable of cell-cell spread, LCMV-immune and naive B6 mice
were challenged with 6 log10 CFU wt rLm-gp.
Splenic bacterial titers were high in challenged naive mice on day 2
postinfection (6.11 ± 1.33 log10 CFU per
spleen). In contrast, rLm-gp-challenged LCMV-immune mice had
significantly lower bacterial loads (2.00 ± 0.41
log10 CFU per spleen, Fig. 1
A). Clearance of rLm-gp in
LCMV-immune mice was associated with the generation of
gp33–41-specific effector CD8 T cells from a memory pool established
by LCMV immunization (Fig. 1, B and C). Effector
and memory CD8 T cells were distinguished on the basis of binding to
1B11, a mAb that binds activation-associated O-glycan
moieties on CD43 (22). The majority of gp33–41-specific
CD8 T cells in LCMV-immunized mice were memory cells, displaying low to
intermediate surface densities of the activated form of CD43. Two days
after rLm challenge of immune mice, most splenic gp33–41-specific CD8
T cells were exhibiting high levels of activated CD43, indicating that
these cells had become effectors (Fig. 1C). Thus, memory CD8
T cells established by LCMV immunization mounted a recall response and
conferred significant protection against wt rLm-gp challenge.
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actA rLm-gp, a rLm strain that both
secretes gp33–41 and has an inframe deletion in the actA
gene. The actA Lm enter and multiply normally within host
cells but do not nucleate actin for locomotion and are unable to spread
directly to neighboring cells (23). Challenge of naive
mice with 7.7 log10 CFU actA rLm-gp
resulted in bacterial loads of 6.06 ± 0.78
log10 CFU per spleen on day 2 postinfection,
similar to day 2 bacterial loads of naive mice infected with wt rLm-gp
(Fig. 1
A). LCMV immunization conferred significant
protection against actA rLm-gp challenge. Bacterial loads
in immune mice were 3.08 ± 0.85 log10 CFU
per spleen, 
1000-fold less than in naive mice (Fig. 1A).
This protection was also associated with the generation of
IFN--producing gp33–41-specific effector CD8 T cells (Fig. 1, B and C).
Although gp33–41-specific primary and recall responses of CD8 T cells
were similar in LCMV-immunized mice challenged with wt and
actA rLm-gp (Fig. 1, B and C), we
performed additional experiments wherein naive and immune mice were
challenged with a mixture of wt and actA rLm-gp. Splenic
bacterial loads for each strain were determined by plating on media
with Em or Km (see Materials and Methods). Mixed infections
allowed direct internally controlled comparisons of protective
immunity. To compare protection against wt rLm-gp and
actA rLm-gp conferred by immunization in the context of
mixed and individual infections, the extent of protection was
calculated for each strain in each experiment by subtracting mean
titers in log10 CFU in immune mice from mean
titers in log10 CFU in naive mice
(10). We observed 4.14 ± 0.87 and 4.11 ± 1.50
log10 CFU protection against wt rLm-gp, and
3.02 ± 1.24 and 3.13 ± 1.25 log10 CFU
protection against actA rLm-gp in individual and mixed
infections, respectively (Fig. 1D). Thus, LCMV immunization
conferred protection against both the wt rLm-gp and actA
rLm-gp strains in the context of mixed infection, and levels of
protection were similar to those observed in individual infections. In
addition, the levels of protection against actA rLm-gp
appear lower than those for wt rLm-gp, although this difference in
protection was not statistically significant (p
= 0.09, Student’s t test). Therefore, our results show that
Ag-specific memory CD8 T cells are capable of mediating clearance of
bacteria that spread cell-cell as well as cell-spread-defective
bacteria.
Perforin-deficient Ag-specific CD8 T cells do not confer significant protective immunity against rLm capable of cell-cell spread
Perforin-dependent CD8 T cell cytotoxicity has been shown to be
involved in protection against wild-type Lm (10). We
hypothesized that the importance of CTL lysis of infected cells in
protective immunity to Lm is related to the ability of this bacterium
to directly spread cell-cell (17). We thus predicted that
protective immunity against bacteria incapable of cell-cell spread
would be less dependent on the cytolytic function of CTL. To determine
the contribution of CTL cytotoxicity to protective immunity against wt
and cell spread-defective rLm, we established a system for comparing
protective immunity conferred by normal and perforin-deficient
gp33–41-specific memory CD8 T cells. Perforin-deficient mice have been
shown to clear MHV, but not LCMV, infections (24, 25).
Thus, gp33–41-specific memory was generated in B6 and PKO mice by
immunization with a rMHV strain expressing the LCMV gp33–41 epitope
within a GFP fusion protein (MHV-gfp gp). Infection of adult B6 and PKO
mice with the rMHV-gfp gp strain resulted in robust splenic CD8 T cell
responses specific to the gp33–41 epitope (Fig. 2, A and B). After
contraction of the responding CD8 T cell populations, gp33–41-specific
memory cells comprised 3–4% of splenic CD8 T cells in both B6 and
PKO mice. The control virus, MHV-gfp, expressing GFP alone, did not
induce a gp33–41-specific CD8 T cell response (data not shown). Viral
clearance in PKO mice was slightly delayed compared with B6 mice, but
virus was undetectable by day 7 postinfection in both B6 and PKO mice,
in agreement with previous reports that perforin-mediated cytolysis is
not required for clearance of MHV infections (24, 25)
(Fig. 2C). Thus, MHV-gfp-gp was cleared by PKO mice and
immunization generated similar levels of gp33–41-specific memory in B6
and PKO mice.
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21 days later with wt
rLm-gp. The specific contribution of gp33–41-specific memory CD8 T
cells to protective immunity was deduced from comparisons with control
mice immunized with MHV-gfp. Splenic bacterial loads and CD8 T cell
responses were determined 65 h after infection with 6.0
log10 CFU wt rLm-gp. MHV-gfp-gp immunization of
B6 mice conferred high levels of protection against challenge with wt
rLm-gp (10,000-fold or 4.27 ± 0.70 log10 CFU
difference between MHV-gfp-gp- and MHV-gfp-immunized mice, Fig. 3A). In contrast, splenic
bacterial loads of wt rLm-gp in MHV-gfp gp-immune PKO mice were similar
to those of control mice (Fig. 3A). Thus, MHV-gfp-gp
immunization of PKO mice conferred little, if any, advantage over
control immunization with respect to protective immunity against rLm-gp
challenge, despite a strong gp33–41-specific recall response.
Approximately 5% of CD8 T cells were gp33–41-specific in both B6 and
PKO mice as measured by intracellular IFN- staining of splenocytes
harvested on day 3 (Fig. 3B). Numbers of gp33–41-specific
CD8 T cells were 105 for both mouse strains
(p = 0.1, Student’s t test). These
data show that the magnitude of the gp33–41-specific recall response
in PKO mice was not significantly different from that of
MHV-gfp-gp-immune B6 mice, therefore, the inability of
gp33–41-specific PKO memory CD8 T cells to protect against wt rLm-gp
was not due to a defect in the recall responses of memory PKO CD8 T
cells but rather due to the absence of the effector function of
perforin. Thus, the majority of protection against wt rLm-gp conferred
by Ag-specific memory CD8 T cells could be attributed to
perforin-mediated cytotoxicity.
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actA rLm
We concluded from the experiments described above that
perforin-dependent cytotoxicity contributes most of the CD8 T
cell-mediated protective immunity against wt rLm infection in our
experimental system. We then sought to examine the role of
perforin-mediated target cell killing by CD8 T cells in the control of
the cell spread-defective actA rLm-gp strain. B6 and PKO
mice immunized with MHV-gfp-gp or the control virus, MHV-gfp, were
challenged with 7.7 log10 CFU actA
rLm-gp. Bacterial numbers and immune responses were assayed 65 h
postinfection. MHV-gfp-gp immunization of B6 mice conferred protection
against challenge with actA rLm-gp (Fig. 4A), in agreement with our
results using LCMV-immunized mice (Fig. 1A). The bacterial
numbers in control-immunized B6 mice were 5.45 ± 0.74
log10 CFU per spleen, 2.76 ± 0.77
log10 CFU more than that in MHV-gfp-gp-immunized
B6 mice (2.68 ± 0.27 log10 CFU per spleen).
Surprisingly, immune PKO mice had significantly lower bacterial burdens
than control PKO mice (3.65 ± 0.36 log10CFU and
5.39 ± 0.49 log10 CFU per spleen in immune
and control mice, respectively, p = 0.0002, Student’s
t test). Thus, PKO mice exhibited considerable protection
against actA rLm-gp (1.78 ± 0.83
log10 CFU). Immunization-conferred protection in
B6 (2.76 ± 0.77) and PKO mice (1.78 ± 0.83) was not significantly
different (p = 0.24, Student’s t
test), demonstrating a minimal contribution of perforin-dependent
killing to protective immunity against actA rLm-gp.
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actA rLm-gp is in
striking contrast to the requirement for perforin against wt rLm-gp.
gp33–41-specific CD8 T cell recall responses were similar among immune
B6 and PKO mice challenged with the wt and actA rLm-gp
strains (Fig. 4B), indicating that differences in protection
were not due to disparities in levels of CD8 T cell responses but
rather due to differing dependence on perforin for protection. In sum,
we found that perforin-dependent CD8 T cell cytotoxicity is essential
for protective immunity against rLm that directly spreads cell-cell
while control of cell spread-defective Lm by CD8 T cells depends on
perforin-independent effector mechanisms. We thus conclude that
perforin-mediated CTL lysis of infected cells counters the effects of
direct cell-cell spread of Lm. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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100-fold less protective than immune splenocytes from normal
mice (18). Protective immunity measured in this original
study was likely conferred, at least in large part, by Lm-specific CD8
T cells, thus suggesting a critical role for perforin in CD8 T
cell-mediated immunity. Later experiments using Ag-specific CD8 T cell
lines derived from PKO mice confirmed the importance of
perforin-mediated immunity while revealing effective
perforin-independent mechanisms of protection (11, 12).
Recent studies have also uncovered a role for perforin in the
regulation of CD8 T cell responses, distinct from its role as an
effector molecule (26, 27).
In the present study, we examined the relative roles of
perforin-dependent CTL cytotoxicity in protective immunity against rLm
strains capable of or deficient in direct cell-cell spread. B6 and PKO
mice were immunized with either recombinant MHV-gfp-gp expressing the
LCMV gp33–41 epitope, or the control virus, MHV-gfp. Immunized mice
were challenged with rLm expressing the gp33–41 epitope and protective
immunity was measured as the difference in bacterial growth between
MHV-gfp-gp and MHV-gfp-immunized mice. Because MHV-gfp-gp and MHV-gfp
differ only by the nonamer epitope, protective immunity in our
experimental system can be attributed exclusively to epitope-specific
CD8 T cells. This is further demonstrated by our finding that
MHV-gfp-gp-immunized mice are not protected against rLm that do not
express the gp33–41 epitope (data not shown). We found that memory CD8
T cells in normal mice were protective against rLm capable of direct
cell-cell spread, while memory CD8 T cells in PKO mice provided little
protection against these bacteria. The impaired clearance of rLm in PKO
mice could only be attributed to the lack of perforin-mediated
cytotoxic effector function in its CD8 T cells, because normal and PKO
mice exhibited similar Ag-specific CD8 T cell memory and recall
responses, as expected from previous reports (12, 28).
Although perforin-deficient memory CD8 T cells conferred little
protective immunity against rLm capable of direct cell-cell spread,
they provided resistance against the cell spread-defective
actA rLm strain, to an extent not significantly different
from that conferred by memory CD8 T cells from normal mice. Thus, the
life cycle of intracellular bacterial pathogens influences the extent
to which perforin contributes to protective immunity. Similarly, it has
been shown that the contribution of CD8 T cell cytolysis to viral
clearance differs depending on the life cycle of the virus in the host.
Although perforin is required for clearance of LCMV infection, it is
completely dispensable for protective immunity to vaccinia virus, VSV,
and Semliki Forest virus (15). These observations
have led to the hypothesis that cytotoxicity is required for the
clearance of noncytopathic viruses (such as LCMV) but not of cytopathic
or lytic viruses (such as vaccinia, VSV, and Semliki Forest)
(15). It is hypothesized that CTL cytotoxicity would have
no or minimal impact on cytopathic viruses because they lyse host cells
in the process of releasing progeny virus, unless CTL cytotoxicity
occurs before virus-induced cell lysis. Such rapid CTL cytolysis of
infected cells may explain the role of perforin in certain lytic viral
infections (e.g. influenza and ectromelia viruses).
Our data point to a new role for perforin-dependent cytolysis in
countering the bacterial virulence strategy of direct intercellular
spread. Based on the results of this study, we propose a model that
stipulates that the importance of perforin-mediated control is
determined by a race between CTL-mediated cytolysis and bacterial
spread (Fig. 5). When the rate of
bacterial spread exceeds the rate of CTL cytolysis, the role of
perforin in control is minimal. This may be the case in primary
listeriosis during which Lm efficiently spread during the development
of the CD8 T cell response. When the rate of bacterial spread is
exceeded by the rate of CTL cytolysis of infected cells, the
contribution of perforin to bacterial clearance becomes apparent.
Perforin-dependent clearance of Lm during secondary infections supports
this notion because memory CTL are known to mount a rapid recall
response. Perforin-mediated cytolysis is likely a trivial component of
protective immunity to intracellular bacteria that do not directly
spread cell-cell, as modeled by the ActA-deficient rLm strain. Because
actA rLm disseminates through an extracellular route
after bacterial growth causes lysis of infected cells, CD8 T
cell-mediated immunity against actA Lm is likely
dependent on cytokines such as TNF and IFN- that may enhance killing
of extracellular bacteria, thereby preventing infection of other cells
(Fig. 5). TNF has been shown to mediate anti-listerial immunity
conferred by perforin-deficient CD8 T cells (11, 14).
Although IFN- is not required for CD8 T cell-mediated immunity
against wild-type Lm (13), a role for IFN- may become
apparent in the control of actA Lm and this possibility
awaits further investigation. Studies in animal models of intracellular
bacterial infections support our hypothesis that the importance of
perforin-mediated cytolysis in protective immunity is related to the
ability of bacteria to directly spread from cell to cell.
Rickettsia sp. are intracytoplasmic bacteria capable of
direct cell-cell spread. In agreement with a prediction of our model,
protective immunity against Rickettsia depends on
perforin-mediated CD8 T cell cytotoxicity (29). Although
CD8 T cells have been established to participate in defense against the
intracellular pathogens Chlamydia pneumoniae and
Mycobacterium tuberculosis, perforin has been shown to play
a minimal role in controlling infections with these bacteria (30, 31). Unlike Lm and Rickettsia, which are
intracytoplasmic pathogens, these bacteria reside within vacuolar
compartments, which may influence the contribution of perforin.
However, perforin-mediated cytolysis should release and expose both
cytosolic and vacuolar bacteria to macrophage and Ab-mediated immune
mechanisms. An alternative interpretation suggested by our model is
that perforin-independent control of Chlamydia
and Mycobacterium relates to their inability to spread
directly from cell to cell without host cell lysis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hao Shen, Department of Microbiology, School of Medicine, University of Pennsylvania, 225 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104. E-mail address: hshen{at}mail.med.upenn.edu
3 Abbreviations used in this paper: Lm, Listeria monocytogenes; VSV, vesicular stomatitis virus; rLm, recombinant Lm; wt rLm, rLm strains in wild-type 10403S background; actA rLm, rLm in cell spread-deficient background; LCMV, lymphocytic choriomeningitis virus; Em, erythromycin; Km, kanamycin; MHV, murine hepatitis virus; GFP, green fluorescent protein; EGFP, enhanced GFP.
Received for publication June 27, 2002. Accepted for publication August 19, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but requires TNF
. J. Immunol. 160:898.. Immunity 3:109.[Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) and PKO mice (
). C,
Kinetics of MHV-gfp-gp infection in livers of infected B6 (
) that
have been activated by cytokines (Cy) such as TNF and IFN-