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Production and Innate Immunity During Listeria monocytogenes Infection in the Absence of NK Cells1
,
*
Institut National de la Santé et de la Recherche Médicale Unit 429, Hôpital Necker-Enfants Malades, Paris, France;
Max Planck Institute for Immunobiology, Freiburg, Germany; and
University of Cape Town, Cape Town, South Africa
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, which is required for the activation of macrophage effector
functions. Mice deficient in the common cytokine receptor -chain
(c-/-), which completely lack NK cells,
were used to examine whether NK cells were essential for resistance to
Listeria infection in vivo. Surprisingly, infected
c-/- mice showed normal innate immunity
and macrophage responses against sublethal Listeria
infection 2 days postinfection. At this time point,
c-/- mice showed increased blood IFN-
levels compared with those in noninfected controls, demonstrating an
NK-independent source of IFN-, which explains early resistance.
Listeria-infected c-/- x
recombinase-activating gene-2-/- double-deficient mice
were unable to produce IFN- and were highly susceptible to L.
monocytogenes. Since T cells, but not B cells, are major
IFN- producers, and c-/- T cells were
found to be efficient IFN- producers in vitro, we conclude from
these results that T cells functionally replace NK cells for the early
IFN- production that is necessary for activating the innate immune
system following infection with L. monocytogenes. This
novel observation in listeriosis underscores how the adaptive immune
response can maintain and influence innate
immunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Listeria induces its own internalization into nonactivated
macrophages and other nonprofessional phagocytes, where the bacteria
survive and replicate. Listeria-infected macrophages respond
by producing IL-12, which, in turn, activates NK cells to release
IFN- (reviewed in Refs. 2–4). IFN- then synergizes with
bacterial products to maximally activate macrophage effector functions
and their secretion of inflammatory cytokines. An important role of the
NK cell/macrophage-IL-12/IFN- loop in listeriosis has been
demonstrated by the increased susceptibility of mice deficient for
IL-12,3 for IFN- (6) or its receptor (7, 8), or for
STAT-1 (9) or ICSBP/IRF2 (10), with the latter two gene products
crucial for the IFN--mediated intracellular signal transduction.
However, IL-12-/- mice survive low dose infection,
implicating an IL-12-independent induction of IFN-.3 In
contrast, macrophage activation by IFN- is crucial to survive the
first week of Listeria infection as evidenced by IFN-
neutralization studies in Listeria-infected wild-type (WT)
mice (11). Moreover, IFN--/- or
IFN-R-/- mice are highly susceptible even to very low
doses of Listeria and die during the first week following
infection (6, 8). We have recently shown that IFN-R-/-
macrophages are impaired to limit the exit of Listeria from
the phagosome to the cytoplasm. These listericidal defects eventually
culminate in unchecked growth and dissemination of the organism,
resulting in extensive organ necrosis and the rapid death of the
infected animals (8). The crucial IFN--dependent macrophage effector
mechanisms that participate in the elimination of Listeria
are not completely elucidated, but involve activation of TNF-
and
NF-IL-6, since mice deficient for these genes are also highly
susceptible to Listeria infection (reviewed in 12 .
The inflammatory response that leads to granulomatous formation appears
necessary for the subsequent adaptive immune response to
Listeria. The cellular components at this stage include
extravasative macrophages, NK cells, and neutrophils that serve to
limit bacterial spread in immunocompetent mice. The activation and
proliferation of Listeria-specific T cells during this later
adaptive immunity eventually clear the invader and lead to acquired
immunity. It is important to note that the presence of ß T cells,
T cells (13), or MHC class I-positive T cells (14) is sufficient
for Listeria clearance. However, the presence and
coordinated action of all T cell subpopulations appear to provide
optimal protection and therefore the most efficient elimination (15).
The common -chain
(c)4 is a
shared cytokine receptor chain that plays a critical functional role in
the receptors to IL-2, IL-4, IL-7, IL-9, and IL-15 (16).
c deficiency in humans results in X-linked SCID,
characterized by a complete block in T cell and NK cell differentiation
and a dramatic susceptibility to various types of infection agents (17, 18). Animal models of X-linked SCID have been generated in mice that
share many features of the human disease phenotype (19, 20, 21).
c-/- mice show a selective absence of NK
cells, T cells, and gut-associated lymphoid tissue. In contrast,
some mature ß T cells and B cells are able to develop, although
the immunologic competence of these residual lymphoid cells remains
untested. It is presumed that c-/- mice
will demonstrate a marked susceptibility to infection due to the
lymphoid developmental defects present in these mice. Moreover, because
of the differential effects of c deficiency on the
development of the various lymphoid subsets, infection of
c-/- mice should reveal whether NK cells,
T cells, or gut lymphoid cells are essential for in vivo immune
responses to certain pathogens. In this report,
c-deficient mice have been used to define the functional
importance of NK cells for innate immunity to L.
monocytogenes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice with a null mutation in the c have been
described previously (21) and were backcrossed four generations on the
C57BL/6 background. Recombinase activating gene-2 (RAG-2) mice (22)
from the 10th generation backcross to C57BL/6 were provided by Dr. B.
Rocha (Institut National de la Santé et de la Recherche
Médicale Unit 345, Paris, France). Mice doubly deficient in
c and RAG-2 were obtained by intercrossing, and
genotypes were determined by PCR on DNA derived from tail snips (primer
sequences available from the authors). Breeding pairs of
IFN-R-/- mice and their WT controls (7) were provided
by M. Aguet (Zurich, Switzerland). All mice were raised in a specific
pathogen-free animal facility (Centre Nationale de la Recherche
Scientifique/CDTA, Orleans, France; or Max Planck
Institute for Immunobiology). Seven- to 12-wk-old mice were
infected with L. monocytogenes and housed in filter-top
cages.
Bacteria and infection of mice
Virulent L. monocytogenes were grown in trypticase-soy broth (Difco, Detroit, MI) as described previously (23). Aliquots of log-phase growing cultures were stored at -70°C until use. For each experiment, a vial was thawed, and bacteria were washed once in saline and diluted in endotoxin-free PBS before injection. Mice were injected i.v. into the tail vein or i.p. with 200 µl of PBS with or without bacteria. The number of viable bacteria in the inoculum and in organ homogenates was determined by plating 10-fold serial dilutions on trypticase-soy broth-agar plates. Plates were incubated at 37°C, and numbers of CFU were counted after 24 h. Heat-killed L. monocytogenes (HKLM) were prepared by incubating bacteria at 60°C for 60 min. Bacteria were pelleted and stored in PBS at -20°C until use.
Histology
Mice were killed by cervical dislocation; their organs were removed, cut in pieces, and fixed in 5% formalin solution. Tissues were dehydrated in ethanol and embedded in paraffin. The 5-µ sections were cut and stained with hematoxylin and eosin or with naphthol-AS-D-chloroacetate-ester for special visualization of neutrophils (24). Listeria were identified by silver staining. Silver stain was used to visualize Listeria (25). All studies were performed using a Zeiss microscope fitted with image analysis software (SIS, Munster, Germany) for the computerized morphometry.
Cell preparation and culture
Splenocytes were isolated aseptically, and E were lysed using hypotonic saline solution. In some experiments, T cells were enriched using MiniMacs isolation columns (Tebu, Paris, France) and anti-CD5-coupled paramagnetic beads according to the manufacturer’s protocol. Cells were cultured in Iscove’s medium (Life Technologies, Paisley, Scotland), supplemented with 10% (v/v) heat-inactivated FCS, 5 x 10-5 M 2-ME, 100 U/ml penicillin, and 100 µg/µl streptomycin. Cells (1–2 x 106 cells/ml) were stimulated in 48- or 96-well plates with anti-CD3 (5 µg/µl; clone 2C11), IL-12 (100 U/ml), or HKLM (2 x 107 CFU/ml). Cell-free supernatants were harvested at different times following incubation at 37°C.
Determination of cytokine levels in blood and supernatants
The production of cytokines was measured using sandwich ELISAs.
Sera or plasma and culture supernatants were used in three- or fivefold
serial dilutions. Appropriate standards (PharMingen, San Diego, CA)
were used in threefold serial dilutions. The coating and biotinylated
detection Abs for IL-1, IL-6, and IL-10 were purchased from
PharMingen, and those for IFN- were obtained from Genzyme
(Cambridge, MA). Alkaline phosphatase coupled to streptavidin (Southern
Biotechnology Associates, Birmingham, AL) was used to detect
biotinylated Abs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing NK cells
NK cells are believed to provide the initial burst of IFN- that
is critical for the macrophage activation that leads to a protective
innate response following infection with L. monocytogenes
(reviewed in Refs. 3 and 12). In the absence of IFN- or its
receptor, Listeria replicates unabated, and mice rapidly
succumb to infection within days (6, 7, 8). Since the c is
required for NK development (19, 21), c-deficient mice
provided us the means to address the role of NK cells (and the
cytokines they produce (e.g., IFN-) in the innate response to
Listeria. Unexpectedly, NK-deficient
c-/- mice were resistant to sublethal
Listeria infection and survived the early course of
infection (beyond day 7) without mortality (Fig. 1
), indicating an efficient innate
response. Listeria-infected mice were subsequently analyzed
on day 2 postinfection, where the innate responses are at their maximum
and where in the absence of IFN- stimulation mice show a
significantly higher bacterial burden (8). The liver and spleen of
infected c-/- mice showed a similar
bacterial burden as infected organs of control mice (Fig. 2) and a similar histopathology,
concerning the size and number of microabscesses in the infected organs
(Fig. 3, a and b),
thus failing to demonstrate any defects in the day 2 response. In
contrast, IFN-R-/- mice show a dramatic inability to
control Listeria at this time point and succumbed to
infection within 4 days (Fig. 1), suggesting that some IFN- had to
be present in infected c-deficient mice to prime the
innate effector cells, such as macrophages. Indeed, circulating levels
of IFN- were detected in the sera of Listeria-infected
c-/- mice at 2 days postinfection,
although the total amount was considerable reduced (13-fold) compared
with that in infected controls (Table I).
We have demonstrated previously that the absolute numbers and phenotype
of splenic and peritoneal macrophages in
c-/- mice were normal, and that
c-deficient macrophages were not impaired in their
abilities to produce inflammatory mediators or to phagocytose
micro-organisms (20). In addition, peritoneal macrophages from
uninfected c-/- mice could produce
considerable amounts of nitric oxide after in vitro culturing
(c-/- macrophages, 70.0 ± 25.8 µM;
WT macrophages, 12.4 ± 8.7 µM). Moreover, macrophages from day
2-infected c-/- mice showed a similar
inflammatory cytokine response after restimulation with HKLM as WT
macrophages (Table II). Because
macrophage activation by IFN- is crucial for some of these
inflammatory responses (8), these results further indicate an
alternative source of IFN--producing cells in
c-/- mice.
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c-/- mice
During the early stages following Listeria infection,
NK cells are the primary IFN- producers. In contrast, primed T cells
are potent in vivo IFN- producers during the late phase (or
adaptive) response to Listeria infection (26). To
investigate the potential protective role of
c-/- T and B cells in the early immune
response to Listeria, we generated
c-/- x RAG-2-/-
double-mutant mice and determined their response to sublethal
Listeria infection. In striking contrast to
Listeria-infected RAG-2- or c-deficient mice,
all c x RAG-2 double-deficient mice succumbed to by day
4 postinfection (Fig. 4), with kinetics
of mortality similar to those of IFN-R-/- mice (see
Fig. 1
). Circulating levels of IFN- were at the limit of detection
in the double-mutant mice (<25 pg/ml) on day 2 postinfection, whereas
c-/- or RAG-2-/- mice showed
a clear increase in serum IFN- (Table I). Moreover,
Listeria-infected c-/- x
RAG-2-/- mice demonstrated a liver pathology identical
with that found following infection of IFN-R-/- mice
(Fig. 3, c and d). Both mutant mouse strains
showed extensive necrotic lesions and liver parenchymal destruction
with dissemination of bacteria. These results 1) point to a critical
role of IFN- in protective innate responses to L.
monocytogenes, 2) rule out the possibility that immature NK cells
were source of IFN- in c-/- mice, and
3) strongly suggest that c-/- T cells are
the early IFN- producers that prime innate responses following
Listeria infection. To address this last point directly, T
cells of naive c-/- mice were purified and
stimulated with anti-CD3, IL-12, or both, and IFN- release into
the culture supernatant was measured. Both normal and
c-/- T cells responded by IFN-
production after stimulation with IL-12 and anti-CD3 (Fig. 5).
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c-deficient mice
Having shown that T cells play an important role in maintaining
innate immunity to Listeria in
c-/- mice, we next examined whether these
T cells were also competent to sterilize a Listeria-infected
c-deficient mouse. It is well established that
elimination of Listeria during the later course of infection
is mediated by Ag-specific T cells (reviewed in 12 . WT and
c- mice were sublethally infected, and on
day 12 postinfection the bacterial burden in liver and spleen was
measured (Fig. 6). Immunocompetent mice
showed low residual bacterial levels in these organs, with nearly
complete sterilization of the Listeria. In contrast,
c-/- mice were clearly defective in
Listeria elimination, harboring up to 106 CFU in
the infected organs, and thus demonstrated a chronic state of
infection. A comparative infection study of RAG-2-/- mice
(with no mature T cells) vs c-/- mice was
next performed. As expected, RAG-2-/- mice survived the
early course of infection, but succumbed during the later infection
period. Interestingly, c-deficient mice showed mortality
kinetics similar to those observed in RAG-2-/- mice (Fig. 7). Moreover, moribund mice of both
mutant strains showed similar histopathology, with many granulomatous
lesions and neutrophil infiltration, harboring Listeria in
the inflammatory foci (Fig. 3, e and f). To
determine the relative degree of T cell dysfunction in
c-/- mice, T cell responses to
alloantigens were examined. c-/- T cells
completely failed to proliferate in response to MHC-disparate
stimulator cells, although control T cells responded normally (data not
shown). Taken together, these results indicate that both alloantigen-
and Ag-specific T cell responses are completely defective in
c-/- mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF- in the early phase of
infection by L. monocytogenes is crucial for the activation
of macrophage effector functions that are required to limit bacterial
growth and control infection (6, 7, 8, 27, 28, 29). The initial source of
IFN- appears to be NK cell derived, and its production is stimulated
by IL-12 produced by resident macrophages following penetration of the
invading micro-organism. This NK/macrophage feedback activation model
of T cell-independent innate resistance (see Fig. 8) has been mainly developed from
extensive Listeria infection studies in SCID mice (2, 3, 30)
and remains the current model to explain innate immunity against
pathogenic infections (31). Despite this apparently important function
of NK cells, a critical question remained concerning alternative
sources of initial IFN- production that may be involved in the early
resistance to Listeria. To unequivocally answer this
question we used c-/- mice, which
completely lack NK cells (19, 21), and showed that these mice were able
to survive the early course of Listeria infection. The
observed innate immunity could be explained by the finding of
considerable circulating levels of IFN- (albeit reduced compared
with those in controls) in the mutant mice during this time. These
results demonstrated that 1) NK cells are not absolutely required for
innate resistance to Listeria; and 2) NK-independent sources
of early IFN- production exist in c-/-
mice.
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during the
anti-Listeria response of c-deficient
mice? Activated T cells are efficient IFN- producers during the
latter specific immune response to Listeria infection, and
we have shown that unprimed c-/--derived
splenic T cells can be stimulated to produce IFN-. Moreover,
Listeria-infected c-/- x
RAG-2-/- double-deficient mice (lacking NK, B, and T
cells) were unable to induce circulating levels of IFN- and
succumbed to Listeria infection with the same
pathophysiology as IFN-R-deficient mice. These results demonstrated
that c-/- lymphocytes were indeed the
source of early IFN- production during innate immune responses to
L. monocytogenes infection. Since B cells do not play a
protective role during Listeria infection, T cells seem to
be the IFN- producers in Listeria-infected
c-/- mice.
It appears that alternative mechanisms exist to prime effector cells of
the innate immune system, which is independent of the classical pathway
that requires macrophage-derived IL-12 acting on NK cells to produce
IFN-. In c-/- mice, activated T cells
produced sufficient amounts of IFN- to maintain macrophage effector
functions, such that early responses to invading micro-organisms (in
this case Listeria) are effective. Although this T
cell-dependent resistance in c-/- mice
appears unrelated to the specific infection, the adaptive immune
response in this way may provide additional nonspecific support
of the innate immune arm. This alternative pathway of T cell-dependent
resistance in innate immunity to L. monocytogenes (see Fig. 8) may have the evolutionary advantage of protecting the host against
secondary infections.
Which T cell subset(s) is able to mediate the observed IFN-
responses, and what mechanisms control the IFN- production? A
variety of T cell subsets are capable of IFN- production, including
Ag-primed ß T cells, T cells, and the NK1.1+
ß T cells (32, 33). These last two T cell types have also been
implicated in the initial responses to pathogens due to their
restricted TCR variability, which has been hypothesized to interact
with nonpolymorphic antigenic determinants on the invading
micro-organism (34). However, T cells and NK-T cells are absent
from the peripheral lymphoid organs of
c-/- mice (19, 21, 35, 36), thereby ruling
out any essential role of these subsets in the anti-listerial
innate response. Because anti-CD3 treatment resulted in IFN-
production from c-/- T cells stimulated
with IL-12 in vitro, TCR cross-linking is probably also required for
optimal innate responses to Listeria in vivo. However, this
hypothesis would predict 1) that Listeria Ag-specific ß
T cells are already present in c-/- mice
and are rapidly reactivated; 2) that ß T cells become activated
oligoclonally by Listeria-produced superantigens; or 3) that
ß T cells in c-/- mice are
constitutively activated through their TCR by some other mechanism. As
we failed to detect cytokine release (IFN-) from
c-/- spleen cell cultures in response to
HKLM (data not shown), it is unlikely that preexisting
Listeria-specific T cells or Listeria
superantigens are responsible for TCR stimulation in vivo.
How, then, might residual c-/- ß T
cells become nonspecifically activated? Two probable mechanisms involve
the crucial role of c in responses to IL-2 and IL-4. The
IL-2 signaling pathway appears necessary for peripheral T cell
homeostasis, as mice deficient in IL-2, CD25 (IL-2R), or CD122
(IL-2Rß) have peripheral T cell activation and proliferation,
autoimmune hemolytic anemia, and colitis (37, 38, 39).
c-/- mice also develop extramedullary
hemopoiesis and colitis (40) (J. P. Di Santo, unpublished
observations), and c-/- ß T cells
have an activated/memory phenotype (40, 41). Therefore, the inability
of c-/- mice to signal via IL-2 may result
in nonspecific T cell activation, potentially toward self Ags. In
addition, because IL-4 polarizes T cells to the Th2 phenotype, the
absence of IL-4 signaling would result in a default Th1 differentiation
with an IFN--producing potential. Together, these two mechanisms may
explain the ability of naive T cells from
c-/- mice to produce IFN-. In a very
recent infection study with an independent
c-/- mouse strain it has been demonstrated
that mutant mice survived Toxoplasma gondii infection due to
sufficient IFN- production. CD4+ T cells were a source
of the crucial early IFN- production (42), consistent with our
proposed mechanism of T cell activation in c-deficient
mice.
In earlier studies, we and others have demonstrated that peripheral T
cells from c-/- mice are poorly functional
in response to mitogen stimulation (19, 21, 43), and we anticipated
that c-/- mice might be unable to
completely eradicate a Listeria infection. Here we
demonstrate that c-/- mice establish
chronic listeriosis following infection, which ultimately overwhelms
and kills the mice. These results confirm the requirement for
functional T cells in the specific anti-listerial immune responses
that sterilize the host. Interestingly, the T cell impairment in
c-/- mice seems to be rather severe, since
the mortality kinetics and histopathology of Listeria in
c-/- mice were similar to those in
RAG-2-deficient mice, which completely lack mature T lymphocytes. Thus,
the mature ß T cells that develop in the absence of
c appear unable to respond in an Ag-specific fashion to
Listeria or alloantigens (this report) or to proliferate in
response to MHC class II-restricted hemagglutinin peptides in the
context of c-/- HNT-TCR transgenic
mice (5) (Å.A. and J.P.D.S., unpublished observations).
Nevertheless, c-/- T cells have an
activated phenotype and accumulate with age (40), suggesting an active,
Ag-driven process. The nature of the stimulatory signals for
c-/- T cells remains to be elucidated.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Frank Brombacher, Groote Schuur Hospital, Immunology Department, H47, Observatory 7925, University of Cape Town, Cape Town, South Africa. E-mail address:
3 F. Brombacher, A. Dorfmüller, J. Magram, J. Ferrante, G. Köhler, A. Wunderlin, K. Palmer, M. K. Gately, and G. Alber. 1998. Interleukin-12 is dispensable for protective immunity against low doses of Listeria monocytogenes. Submitted for publication.
4 Abbreviations used in this paper: c, common -chain; RAG-2, recombinase-activating gene-2; HKLM, heat-killed Listeria monocytogenes; WT, wild type.
Received for publication January 26, 1998. Accepted for publication July 17, 1998.
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M. J. Skeen, E. P. Rix, M. M. Freeman, and H. K. Ziegler Exaggerated Proinflammatory and Th1 Responses in the Absence of gamma /delta T Cells after Infection with Listeria monocytogenes Infect. Immun., December 1, 2001; 69(12): 7213 - 7223. [Abstract] [Full Text] [PDF]
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K. A. Remer, T. W. Jungi, R. Fatzer, M. G. Tauber, and S. L. Leib Nitric Oxide Is Protective in Listeric Meningoencephalitis of Rats Infect. Immun., June 1, 2001; 69(6): 4086 - 4093. [Abstract] [Full Text] [PDF]
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Y. Jin, L. Dons, K. Kristensson, and M. E. Rottenberg Neural Route of Cerebral Listeria monocytogenes Murine Infection: Role of Immune Response Mechanisms in Controling Bacterial Neuroinvasion Infect. Immun., February 1, 2001; 69(2): 1093 - 1100. [Abstract] [Full Text] [PDF]
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S. Bregenholt, P. Berche, F. Brombacher, and J. P. Di Santo Conventional {{alpha}}{{beta}} T Cells Are Sufficient for Innate and Adaptive Immunity Against Enteric Listeria monocytogenes J. Immunol., February 1, 2001; 166(3): 1871 - 1876. [Abstract] [Full Text] [PDF]
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G. Lertmemongkolchai, G. Cai, C. A. Hunter, and G. J. Bancroft Bystander Activation of CD8+ T Cells Contributes to the Rapid Production of IFN-{{gamma}} in Response to Bacterial Pathogens J. Immunol., January 15, 2001; 166(2): 1097 - 1105. [Abstract] [Full Text] [PDF]
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 C. Soudais, T. Shiho, L. I. Sharara, D. Guy-Grand, T. Taniguchi, A. Fischer, and J. P. Di Santo Stable and functional lymphoid reconstitution of common cytokine receptor gamma chain deficient mice by retroviral-mediated gene transfer Blood, May 15, 2000; 95(10): 3071 - 3077. [Abstract] [Full Text] [PDF]
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T. Fukao, S. Matsuda, and S. Koyasu Synergistic Effects of IL-4 and IL-18 on IL-12-Dependent IFN-{gamma} Production by Dendritic Cells J. Immunol., January 1, 2000; 164(1): 64 - 71. [Abstract] [Full Text] [PDF]
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B. Bouchard, C. J. Ormandy, J. P. Di Santo, and P. A. Kelly Immune System Development and Function in Prolactin Receptor-Deficient Mice J. Immunol., July 15, 1999; 163(2): 576 - 582. [Abstract] [Full Text] [PDF]
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 T. Ohteki, T. Fukao, K. Suzue, C. Maki, M. Ito, M. Nakamura, and S. Koyasu Interleukin 12-dependent Interferon {gamma} Production by CD8{alpha}+Lymphoid Dendritic Cells J. Exp. Med., June 21, 1999; 189(12): 1981 - 1986. [Abstract] [Full Text] [PDF]
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400-fold reduced
CFU number in liver, and most mice had eliminated
Listeria in spleen (<10 CFU). The mean value is
indicated by a horizontal line.
