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Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
. We did not find a role for
IL-12, IL-10, or nitric oxide. Adoptive transfer studies showed a
decisive role for both CD4+ and CD8+ T cells
for an effective immune response, i.e., clearance of bacteria,
granuloma formation with lymphocytes, and disappearance of
microabscess. Clearance of Listeria was induced by transfer
of CD8+ T cells from mice with targeted disruption of the
IFN- structural gene (IfgTM1KO), even in the presence of
neutralizing mAb to IFN-. In marked contrast, transfer of
CD4+ T cells from IfgTM1KO mice exacerbated the infection
in the chronically infected SCID mice, resulting in increased mortality
with dissolution of the granulomas and severe hepatic infection with
neutrophil infiltration. Thus, these data indicate that both
IFN--dependent and -independent mechanisms are operative in the
context of a chronic listerial infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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released by NK cells (3). However, SCID mice did not develop
sterilizing immunity, harboring Listeria monocytogenes
organisms for many weeks.
This study evaluates the chronic carrier state of Listeria
monocytogenes infection in the SCID mouse. We wanted to compare
the parameters of natural resistance in the chronic infected SCID mouse
with those from SCID or normal mice with acute listeriosis. The purpose
was to examine whether the basic parameters of resistance would change
during chronic infection. Chronic infection with many intracellular
pathogens may not result in the complete elimination of the microbe,
leading to the speculation of whether the state of resistance and
immunity changes and/or deteriorates with time. A second component that
we evaluated here is the role of the T cells transferred to SCID mice
that are chronically infected. Is a chronic Listeria state
of infection effective in priming lymphocytes, and if so, how is the
lymphocyte carrying out sterilizing immunity? Along these lines, it is
important to stress that although macrophage activation by IFN- was
a sine qua non for Listeria protection (1, 4), this
activation did not bring about sterilizing immunity, which required T
cells. The results of Listeria monocytogenes infection in
the SCID mouse are highly eloquent in this regard: the development of
extensive macrophage activation with participation of nitric oxide
(NO.)3, (5), yet
a chronic state of infection developed in which the infective organism
and the host entered into a state of apparent equilibrium.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C.B-17/ICR SCID and C.B-17/ICR (C.B-17) mice (6) were bred in
pathogen-free conditions at Washington University (St. Louis, MO). Mice
were used at 6 to 12 wk of age. BALB/c mice and BALB/c-IfgTM1 mice were
purchased from The Jackson Laboratory (Bar Harbor, ME) and used at 6 to
8 wk of age. The latter mice did not express IFN- as a result of a
genetic ablation of the structural gene for IFN- (7).
Abs and reagents
RB6-8C5 is a rat mAb (IgG2b) specific for murine neutrophils
initially produced by R. Coffman (DNAX, Palo Alto, CA) (8, 9, 10). The
anti-IL-10 mAb, 2A5, and Red-T, a hamster anti-IL-12 mAb, were
previously described and used by Tripp, Beckerman, and Unanue as
described in Reference 11 and Tripp, Kanagawa, and Unanue, as described
in Reference 12. Rat mAb was purified by affinity chromatography using
standard procedures. Hamster anti-mouse TNF mAb, TN3-19.12 (13),
and hamster anti-mouse IFN- mAb, H22.1 (4) were kindly donated
by Dr. R. D. Schreiber (Washington University, St. Louis, MO).
These reagents were used as purified Ig and were endotoxin free, as
determined by the Limulus assay (Whittaker Bioproducts,
Walkersville, MD). RL172 (anti-CD4) and 3.155 (anti-CD8) were
used as culture supernatants. FITC-conjugated rat anti-CD4 mAb
(clone CT-CD4) and FITC-conjugated rat anti-CD8 mAb (clone CT-CD8a)
were purchased from Caltag Labs., San Francisco, CA. Aminoguanidine
hemisulfate salt (Sigma Chemical Co., St. Louis, MO) was injected twice
daily for 6 days (5) at a concentration of 6 mg in 0.5 ml of
pyrogen-free saline.
Generation of splenic cells
Immune cells were derived from mice after a primary or a
secondary immunization. For primary infection, C.B-17 mice were
immunized i.p. with 5 x 103 viable
Listeria (strain EGD), in 0.2 ml of pyrogen-free saline
(LD50:104). The secondary infection was
initiated 14 days after the primary infection with 5 x
104 live Listeria, injected i.p. in 0.2 ml of
pyrogen-free saline. All the mice survived the secondary infection with
this dose of Listeria compared with naive mice, all of which
died. In experiments utilizing unfractionated splenic cells from naive
mice, single cell suspensions were made and RBC were lysed with Tris
ammonium chloride. Cells were sieved through a Nytex filter (Becton,
Dickinson, Lincoln Park, NJ), and resuspended at 5 x
108 cells per ml in pyrogen-free saline. For the adoptive
transfer of T cell subsets, after lysis of the RBC, negative selection
of CD4+ and CD8+ T cells from primed or naive
mice was conducted by incubating 5 x 107 cells/ml
with 10% v/v of undiluted culture supernatants of anti-CD4 (RL172)
and anti-CD8 (3.155) Ab and 1:10 dilution of rabbit serum as a
source of complement (Low-tox rabbit complement; Pel-Freeze Biologics,
Rogers, AR) for 45 min at 37°C. Two rounds of treatment were
performed. This protocol consistently resulted in reduction of the
targeted subsets to <2% of the total spleen cells as assessed by flow
cytometric analysis using FITC-conjugated anti-CD4 and anti-CD8
mAbs. Subsequently, cells were sieved through a Nytex filter, and
resuspended at 5 x 108 cells per ml in pyrogen-free
saline (see Fig. 6
for one representative result that includes data on
the treated cells). (Treatment with both anti-CD4 and anti-CD8
essentially eliminated all CD3-bearing T cells. Operationally, the
CD4-depleted spleen cells are called CD8 T cells and vice versa.)
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The SCID mice were injected i.v. with 104Listeria, usually 14 to 30 days before transfer of 108 immune splenic cells. In some experiments, spleen cells from naive mice were transferred. The number of Listeria in the organs of recipient SCID mice were quantitated at the time points indicated in the figure legends, i.e., 3, 6, and 15 days. Spleens and livers were homogenized in 10 mM PBS containing 0.05% Triton X-100, and then were plated as serial dilutions onto brain-heart infusion agar (Difco, Detroit, MI). Bacterial colonies were quantitated after 24 h of growth at 37°C. Immune spleen cells were obtained from CB.17 mice either 10 days following a primary infection or 3 days following a secondary challenge.
Histologic and electron microscopic procedures
At various times after Listeria infection, SCID mice were killed, and sections of liver and spleen were fixed for 24 h in 10% neutral-buffered formalin. Sections were taken from chronically infected SCID mice following i.p. administration of aminoguanidine hemisulfate or anti-cytokine Abs. Similarly, sections from chronically infected mice were taken following adoptive transfer of unfractionated or negatively selected CD4+ or CD8+ splenic cells. The tissues were routinely processed for staining with hematoxylin and eosin. Samples for electron microscopy were fixed in cacodylate-buffered glutaraldehyde, postfixed in OsO4, stained en-bloc with uranyl acetate, and infiltrated with a methacrylate resin. Thin sections were mounted as 200-mesh copper or nickel grids, stained with lead citrate, and examined with a Philips CM10 electron microscope. (Philips Electronic Instruments Co. Eindhoven, The Netherlands).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To establish a model of chronic infection, SCID mice were infected
i.v. with 104 Listeria and the number of
viable organisms in the spleen and liver determined in groups of mice
at various times after infection. Figure 1 shows that the mice were unable to
eliminate the Listeria from the liver, with the bacterial
numbers ranging from 0.1 x 104 to 7.7 x
105. Similar results were obtained in the spleen, with the
Listeria counts ranging from 0.1 x 104 to
5.4 x 105. After 28 days, a proportion of mice
(10–20%) died of Listeria infection.
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A). By day 7, a
granulomatous lesion was observed that essentially consisted of a
compact collection of mononuclear phagocytes, devoid of lymphoid cells
(Fig. 2B). From day 14 to day 60, of a total of 20 to
30 lesions per section, about 95% were granulomas and 5% were
microabscesses. Thus, microabscesses were always found, but these
constituted a minor component after the first 5 days, up to the 60 days
of observation. In the spleen, the histologic picture progressed from a
periarteriolar collection of neutrophils in early infection to
granulomas of different sizes localized in the white pulp after day 14
of infection, and mixed with foci of neutrophils.
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C). Only one
Listeria was found in the cytosol. Elements essential for maintaining a Listeria-carrier state in the chronically infected SCID Mice
Previous work with SCID mice showed that neutrophils (8), IL-1
(16), IFN- (1), TNF- (17), IL-12 (18), and NO.
(5) were necessary for resistance to acute Listeria
infection. Similar requirements were found for acute listeriosis in
normal mice (reviewed in 2 . In this first report, we evaluated
the roles of two major cytokines, IFN- and TNF, plus those of IL-12,
IL-10, and NO.. Specific inhibitors were administered
shortly before initiation of infection, or in the case of
NO., 2 days after i.p. inoculation with live organisms. We
sought to examine the role of these mediators in a chronic infective
state by the i.p. administration of anti-cytokine Abs to SCID mice
infected with 104 Listeria 14 to 30 days
earlier. Aminoguanidine hemisulfate was injected twice daily, as
described in Materials and Methods,
for the purpose of inhibiting the inducible NO. synthetase.
In both cases the mortality, bacterial counts, and histology of the
livers were assessed at 40, 96, or 144 h after treatment. The
course of the infection was easier to follow in the liver, where the
two histologic lesions were easily outlined.
Administration of anti-granulocyte (RB6-8C5) mAb had a profound
effect by increasing splenic and liver Listeria burden (Fig. 3A). This effect was
seen as early as 40 h, e.g., the liver Listeria numbers
in two mice at 40 h was 4.4 x 106 and 6.2
x 106. There was also an increase in mortality of these
mice; in two separate experiments, three of five and two of five mice
given anti-granulocyte mAb died by day 6. Similar enhancement of
liver and splenic bacterial loads, but with a delayed time kinetics
(after 2 days) was seen after administration of anti-TNF-
(TN3-19.12) and anti-IFN- (H22.1) mAbs (Fig. 3, A and
B).
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C). Inhibition of
endogenous NO. by injection of aminoguanidine hemisulfate
also had no effect on the in vivo growth of Listeria (Fig. 3D). Similarly, inhibition of IL-12 by administration
of anti-IL-12 mAb, Red-T (250 µg) had no effect on the bacterial
load (Fig. 3D).
The histologic lesions in mice depleted of neutrophils or given the
mAbs that neutralized IFN- or TNF- were essentially similar in
that the net result was infection of hepatocytes. Histology of livers
from mice treated with RB6-8C5 showed large confluent zones of
liquefactive necrosis, with Listeria present extracellularly
and in necrotic hepatocytes in the center (Fig. 4A). The livers of mice
treated with anti-TNF- mAb also showed abundant
Listeria present in the microabscess with a viable rim of
hepatocytes around a central necrotic area (Fig. 4B).
Neutrophils were present to variable degrees in the infective foci.
Histologic sections from anti-IFN- mAb (H22.1)-treated mice also
showed a dramatic increase in the number and size of neutrophilic
lesions (Fig. 4C). Very importantly, granulomas were
no longer identifiable in any of these mice. A Gram stain demonstrated
abundant extracellular Listeria, and in the hepatocytes
adjacent to the microabscess (Fig. 4D). The spleen
lesions in anti-TNF- or anti-IFN--treated mice were
characterized by numerous foci of neutrophils dispersed through both
the red and white pulp.
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The mAbs were tested at doses that exceeded their neutralizing effect by two- to threefold. Indeed, the efficacy of the anti-IL-12 mAb was tested by injecting the Abs 1 h before acute infection of SCID mice with live Listeria (5 x 103), as previously described (18). Similarly, aminoguanidine hemisulfate was administered shortly after (day 0) i.p. inoculation of SCID mice with live Listeria, as was described by Beckerman et al. (5). Both treatments resulted in a significantly higher number of cultured Listeria in spleens and livers of infected mice (i.e., for aminoguanidine and Red-T; >2 log increase over control mice). The anti-IL-10 mAb had been previously evaluated (11).
Adoptive transfer of immune or naive splenic cells is protective
Having evaluated some of the parameters important in maintaining a
carrier state in chronically infected SCID mice, we examined whether
adoptive transfer of immune splenic cells could produce sterilizing
immunity. Immune splenic cells were derived from immunocompetent C.B-17
mice 10 days following a primary i.p. infection with 5 x
103 Listeria. Figure 5A shows that by day 6
post-transfer of 108 splenic cells, the Listeria
infection was substantially cleared (the minimal level of detection of
Listeria in organs is 
102). Similar results
were obtained by transfer of immune splenic cells derived from mice
that received a secondary challenge 14 days later with 5 x
104 Listeria. (Transfer of 5 x
107 splenic cells also led to clearance of
Listeria but there was greater variability among the mice.)
The protection was specifically mediated by T cells since immune
splenic cells depleted of both CD4+ and CD8+
cells with Ab and complement treatment were not effective (Fig. 5B) in clearing the chronic infection.
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C shows that 108 naive cells were equally
effective in protecting immunity, though with a delayed time kinetic
(by day 15 instead of day 6).
Histologic analysis of post-transfer livers showed well-formed,
medium-sized to large granulomas, with lymphocytes (Fig. 5D). There was complete disappearance of the
microabscess. Thus, specific immunity to Listeria could be
induced by adoptive transfer of either immune or naive T cells from
immunocompetent mice.
Both CD4+ and CD8+ T cells can resolve a chronic Listerial infection
Our intent was to determine whether CD4+ and
CD8+ T cell subsets were effective in clearing
Listeria in chronically infected mice. Figure 6A shows the results of
transfers of spleen cells from naive C.B-17 mice depleted of either
CD4+ or CD8+ T cells by treating them with mAb
and complement treatment in vitro. The negatively selected cells led to
sterilizing immunity, by day 15, and to granulomas containing
lymphocytes. Granulomas identical to those shown in Figure 5D were seen following transfer of either CD4+
or CD8+ T cells.
Figure 6B shows that treatment with anti-CD4 or
anti-CD8 mAb removed the targeted cell population, as determined by
cytofluorometric analysis of the splenic cells. We also followed the
course of these negatively selected splenic cells in vivo after
adoptive transfer into chronically infected mice. We found that the
expected T cell depletion was essentially complete at 14 days
post-transfer, i.e., in mice given negatively selected CD4+
T cells, there was no residual staining for CD8, and vice versa. Thus,
both CD4+ and CD8+ T cells were effective in
mediating an antibacterial immune response. We have not conducted a
titration of each T cell subset to determine their relative
efficiency.
T cell protection is mediated by both IFN--dependent and
-independent mechanisms: identification of a T cell suppression of
resistance
We have now performed a set of initial experiments attempting to
characterize the mode of action of T cells. We report here the results
of using T cells lacking expression of IFN-. Naive splenic cells
from homozygous IFN--null gene, i.e., knock-out (KO) mice (IfgTM1)
were transferred into chronically infected SCID mice. The IFN- gene
KO mice have been shown to be exquisitely sensitive to primary
infection with Listeria (19). As shown in Figure 7 (A and
B), transfer of 108 naive splenic cells
from IFN- gene KO mice protected as efficiently as the spleen cells
from wild-type BALB/c controls.
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gene KO mice were also
effective. We also transferred CD8+ T cells from IFN-
gene KO mice into chronically infected SCID mice in the presence of
neutralizing Ab to IFN- (H22.1). Figure 7C shows that
CD8+ T cells protected when the neutralizing mAb H22.1 was
administered either at 5 or 10 days after transfer of T cells. Mice
given mAb H22.1 before adoptive transfer of CD8+ T cells
from IFN- KO mice were not protected and died by day 15. Groups of
control chronically infected mice not transferred with cells and
injected by mAb H22.1 at day 0 were susceptible to infection as was
also shown in Figure 3.
Interestingly, transfer of CD4+ T cells from IFN- gene
KO animals led to different results, with exacerbation of disease and
increased mortality. In three experiments, 7 of 17 mice had died by 2
wk after transfer. This compared with 0 of 11 of control infected mice
not given CD4+ T cells, or 0 of 12 transferred with
wild-type CD4 T cells. Histology of liver lesions from these mice
revealed multiple large neutrophilic abscesses with massive infection
of liver cells admixed with neutrophils and lymphocytes. Granulomas
were not present. The histologic picture was identical to that found in
mice given anti-TNF or anti-IFN- mAb (Fig. 4, B
and C). Likewise, the spleen contained numerous foci
of infection rich in neutrophils.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
TNF-. 2) Lymphocytes from naive donors could be transferred and
primed in the chronic infected mice, indicating that Ag presentation
could take place. 3) CD8+ T cells could bring about
sterilizing immunity without the apparent participation of IFN-. 4)
In contrast to CD8+ T cells, CD4+ T cells from
IFN- gene KO animals have an active suppressive role, bringing about
a profound disturbance of the fine equilibrium between the host and the
microbe.
The livers of the chronically infected SCID mice exhibited two distinct
types of pathologic lesions, i.e., microabscess and a granuloma, the
latter composed of a compact collection of mononuclear cells without
lymphocytes. Most of the lesions in chronic infection were of the
latter type. We believe that there is an equilibrium between both of
the lesions, with the microabscess representing a "spillover" of
Listeria from the granuloma. This equilibrium is indeed
maintained by neutrophils and macrophages, and by at least two
cytokines (IFN- and TNF). It is likely that the granulomas of the
SCID mouse may not be effective in limiting the spread of
Listeria. Once Listeria escapes the granuloma, it
enters the hepatocyte as it occurs in the early blood-born infection.
In the hepatic parenchymal cells, neutrophils represent the first, if
not only, line of defense, limiting the extent of growth and
dissemination of Listeria. Ample precedent for this
observation has been found in the many reports demonstrating the
effects of neutrophil depletion in acute listeriosis (8, 9, 10). In the
framework of chronic infection in the SCID mice, depletion of
neutrophils resulted in increased mortality, extensive hepatic
colonization, and pronounced exacerbation of infection, reaffirming
that neutrophils play a major role in controlling the intrahepatocyte
infection. Thus, the new information herein is showing, first, the
continuous interplay between these two forms of inflammation that
involve neutrophils and macrophages and, second, the leakiness, or
partial ineffectiveness, of the chronic granuloma in the absence of
effective T cell immunity.
A second feature to note in the context of the chronic infection
was the requirement of IFN- and TNF-. Neutralization of IFN-
and TNF- resulted in the loss of the granuloma <—> microabscess
equilibrium, skewing the process toward infection of the hepatocytes.
Although we did not evaluate the cellular source of either of the
cytokines, we presume that NK cells are involved, as in the acute
infection. IFN- is likely to be maintaining the activated macrophage
state as evaluated previously in the acute infection. The exact role of
TNF is not clear. TNF, together with IL-12, is required for NK cells to
produce IFN-. Previously, we found that the effects of anti-TNF
Abs in vivo could not be entirely corrected by IFN-, indicating that
its target may be more than one cellular locus (18).
We found that the process of resistance in the chronic state was not using IL-12 in contrast to its central role in acute listeriosis both in normal and SCID mice (3, 12, 18). Similar results were found in chronic response to Toxoplasma gondii by Gazzinelli et al. (20). Our laboratory had also previously noted that the secondary response to Listeria in normal mice was considerably less affected by IL-12 (12). Also important to note is that the maintenance of chronic resistance was not affected by neutralization of NO.. This is in contrast to the role of NO. in the early stage of Listeria infection (5, 21). Neutralization of IL-10 also had a minimal effect on bacterial replication or liver morphology of Listeria-infected mice. At this point we cannot distinguish whether these molecules were not produced or simply were produced but were not functionally relevant.
The granulomatous lesion in chronic Listeria infection
showed several other interesting features. Our results with electron
microscopic studies of the liver lesion at day 21 showed
Listeria in membrane-bound vacuolar structures within
mononuclear phagocytes and not in the cytoplasm. Moreover, the majority
of the bacteria appeared intact. In an experiment run in parallel with
the present ones we found, as expected, that in early infection many of
the Listeria were found in the cytosol of macrophages,
surrounded by the typical condensation of actin fibrils. Thus, the
state of the infectious process is one feature that conditions the
intracellular location of this microbe. The explanation may lie in the
study by Portnoy et al. (22), indicating that IFN- activation of
resident peritoneal macrophages in culture prevented escape of
Listeria from the phagosome.
Another observation that is relevant in the context of the localization of Listeria is the protection conferred by CD8+ T cells. We had previously argued that the localization of Listeria in the cytosol was the main factor that determined the activation and involvement of CD8 T cells (23). But as shown herein, CD8 T cells were activated even with limited localization of Listeria to the cytosol. Of course, there are quantitative issues here that need to be taken into consideration. It is possible that the extent of T cell priming may vary greatly depending on the amounts of Listeria in cytosol and/or in vacuoles. Regardless, the results do make a point that the relationship in vivo between localization of the microbe and the resultant CD4 or CD8 response may not be absolute. Intravesicular microbes have been shown to be effective in donating peptides for class I MHC binding (24), an issue that is supported by the present findings.
The transfer of naive T cells and the induction of protective immunity
indicates that the APC in chronically infected mice were still
effective in priming. Experiments presented in this study clearly
showed that both CD4+ and CD8+ T cells could
contribute equally to the elimination of Listeria and
granuloma (with admixed lymphocytes) formation, although detailed
quantitative comparisons were not performed. Protection mediated by
CD8+ T cells, as shown in earlier studies from Bevan’s
laboratory (19, 25), can take place by an IFN--independent pathway,
presumably via perforin-mediated cytotoxicity. We are currently
investigating the role of CD8+ T cells, which could resolve
the infection either by cytotoxic mechanisms, or could modulate the
inflammatory response. In the present study, although we can conclude
that CD8+ T cells operated without production of their own
IFN-, nevertheless a participation of endogenous IFN- cannot be
entirely ignored. The CD8+ T cells did bring about
protection if by the fifth day IFN- was neutralized by mAb, but this
did not occur when neutralization took place earlier. In the case of
the Harty and Bevan experiment (19), they found CD8+ T
cells transferring protection to IFN- KO mice, ruling out
cooperativity with IFN-.
However, it is noteworthy that the secondary response in conventionally
immunized mice was highly susceptible to neutralization of IFN-
(12). Clearly, in the Harty and Bevan experiments (19), which used
well-primed CD8 T cells, and in ours, herein, using a contained
infection, the CD8 T cells could operate well. In contrast, the
systemic challenge in a resting mouse with memory T cells may impose
more demands on the cellular system and require macrophage activation
via IFN-. Experiments in progress are addressing how
CD8+ T cells operate in producing sterilizing immunity.
This requirement of IFN- is no more eloquent in the results with
CD4+ T cells from IFN- KO mice. The results of adoptive
transfers with CD4+ T cells from IFN- gene KO mice were
dramatic: a major suppressive effect that altered the balance between
granulomatous and neutrophilic lesions. This suppressive effect was
superseded when the CD4 cells were mixed with CD8 T cells, although at
this time we have not explored using different ratios of one or the
other. At face value, the protective role of CD8 T cells-IFN- KO
predominated. How the CD4 T cells lacking IFN- production are
operating is now under evaluation. Perhaps they directly or indirectly
produce negative regulatory cytokines (like IL-10) or perhaps they
differentiate to Th2 subsets that produce cytokines like IL-4 that may
inhibit the granuloma. Regardless, these in vivo experiments
demonstrate with great eloquence the profound suppressive effect of
lymphocytes in disturbing a fine balance of chronic infection. The
present series of results poise our investigations into the physiology
of a chronic infective state and the nature of the regulation exhibited
by T cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Emil R. Unanue, Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110.
3 Abbreviations used in this paper: NO., nitric oxide; KO, knock-out.
Received for publication July 21, 1997. Accepted for publication September 23, 1997.
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S. E. F. D'Orazio, M. J. Troese, and M. N. Starnbach Cytosolic Localization of Listeria monocytogenes Triggers an Early IFN-{gamma} Response by CD8+ T Cells That Correlates with Innate Resistance to Infection J. Immunol., November 15, 2006; 177(10): 7146 - 7154. [Abstract] [Full Text] [PDF]
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M. A. Bergman, L. A. Cummings, R. C. Alaniz, L. Mayeda, I. Fellnerova, and B. T. Cookson CD4+-T-Cell Responses Generated during Murine Salmonella enterica Serovar Typhimurium Infection Are Directed towards Multiple Epitopes within the Natural Antigen FliC Infect. Immun., November 1, 2005; 73(11): 7226 - 7235. [Abstract] [Full Text] [PDF]
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D. R. Roach, H. Briscoe, B. M. Saunders, and W. J. Britton Independent Protective Effects for Tumor Necrosis Factor and Lymphotoxin Alpha in the Host Response to Listeria monocytogenes Infection Infect. Immun., August 1, 2005; 73(8): 4787 - 4792. [Abstract] [Full Text] [PDF]
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V. Boyartchuk, M. Rojas, B.-S. Yan, O. Jobe, N. Hurt, D. M. Dorfman, D. E. Higgins, W. F. Dietrich, and I. Kramnik The Host Resistance Locus sst1 Controls Innate Immunity to Listeria monocytogenes Infection in Immunodeficient Mice J. Immunol., October 15, 2004; 173(8): 5112 - 5120. [Abstract] [Full Text] [PDF]
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 L. Cao, C. A. Hudson, and D. A. Lawrence Immune Changes during Acute Cold/Restraint Stress-Induced Inhibition of Host Resistance to Listeria Toxicol. Sci., August 1, 2003; 74(2): 325 - 334. [Abstract] [Full Text] [PDF]
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S. Vollstedt, M. Franchini, H. P. Hefti, B. Odermatt, M. O'Keeffe, G. Alber, B. Glanzmann, M. Riesen, M. Ackermann, and M. Suter Flt3 Ligand-treated Neonatal Mice Have Increased Innate Immunity Against Intracellular Pathogens and Efficiently Control Virus Infections J. Exp. Med., March 3, 2003; 197(5): 575 - 584. [Abstract] [Full Text] [PDF]
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M. Neighbors, X. Xu, F. J. Barrat, S. R. Ruuls, T. Churakova, R. Debets, J. F. Bazan, R. A. Kastelein, J. S. Abrams, and A. O'Garra A Critical Role for Interleukin 18 in Primary and Memory Effector Responses to Listeria monocytogenes That Extends Beyond Its Effects on Interferon {gamma} Production J. Exp. Med., August 6, 2001; 194(3): 343 - 354. [Abstract] [Full Text] [PDF]
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C. Pope, S.-K. Kim, A. Marzo, K. Williams, J. Jiang, H. Shen, and L. Lefrancois Organ-Specific Regulation of the CD8 T Cell Response to Listeria monocytogenes Infection J. Immunol., March 1, 2001; 166(5): 3402 - 3409. [Abstract] [Full Text] [PDF]
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P. Zhou, B. L. Freidag, C. C. Caldwell, and R. A. Seder Perforin Is Required for Primary Immunity to Histoplasma capsulatum J. Immunol., February 1, 2001; 166(3): 1968 - 1974. [Abstract] [Full Text] [PDF]
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D. W. White, V. P. Badovinac, X. Fan, and J. T. Harty Adaptive Immunity against Listeria monocytogenes in the Absence of Type I Tumor Necrosis Factor Receptor p55 Infect. Immun., August 1, 2000; 68(8): 4470 - 4476. [Abstract] [Full Text] [PDF]
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V. P. Badovinac and J. T. Harty Adaptive Immunity and Enhanced CD8+ T Cell Response to Listeria monocytogenes in the Absence of Perforin and IFN-{gamma} J. Immunol., June 15, 2000; 164(12): 6444 - 6452. [Abstract] [Full Text] [PDF]
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 P. S. Myung, J. L. Clements, D. W. White, Z. A. Malik, J. S. Cowdery, L.-A. H. Allen, J. T. Harty, D. J. Kusner, and G. A. Koretzky In vitro and in vivo macrophage function can occur independently of SLP-76 Int. Immunol., June 1, 2000; 12(6): 887 - 897. [Abstract] [Full Text] [PDF]
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B. T. Edelson, P. Cossart, and E. R. Unanue Cutting Edge: Paradigm Revisited: Antibody Provides Resistance to Listeria Infection J. Immunol., October 15, 1999; 163(8): 4087 - 4090. [Abstract] [Full Text] [PDF]
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D. W. White, A. MacNeil, D. H. Busch, I. M. Pilip, E. G. Pamer, and J. T. Harty Perforin-Deficient CD8+ T Cells: In Vivo Priming and Antigen-Specific Immunity Against Listeria monocytogenes J. Immunol., January 15, 1999; 162(2): 980 - 988. [Abstract] [Full Text] [PDF]
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