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*
Clinical Immunology Section, Laboratory of Clinical Investigation, and
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
and/or direct cytolytic activity
by T and NK cells. In this regard, although previous work has clearly
demonstrated a critical role for IFN- and TNF- in limiting fungal
growth in primary HC infection, less is known regarding the role of
cytolytic mechanisms. The studies reported here first address the role
of perforin in mediating immunity to HC. Remarkably, perforin-deficient
knockout (PfKO) mice were shown to have accelerated mortality and
increased fungal burden following a lethal or sublethal primary
challenge. These data established an essential role for perforin in
primary immunity systemic HC infection. Interestingly, depletion of
CD8+ T cells in PfKO mice caused a further increase in
fungal burden and accelerated mortality, suggesting a
perforin-independent role for CD8+ T cells. Moreover,
adoptive transfer of CD8+ T cells from PfKO mice into
IFN--/- mice caused a reduction in fungal burden
following infectious challenge compared with control
IFN--/- mice. Together, these data suggest that
CD8+ T cells can mediate immunity to HC through both
perforin-dependent and -independent mechanisms. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism by which the cellular immune response is able to control
infection by a variety of intracellular pathogens has been an area of
intense interest. This process involves an interaction between the
innate and acquired immune responses and involves both
cytokine-dependent and -independent mechanisms. First, with regard to
cytokine-dependent mechanisms, IL-12-dependent production of IFN-
has been shown to be critical for protection following primary
infection in bacterial (Listeria monocytogenes)
(3), fungal (HC) (4, 5), and parasitic
(Leishmania major) (6) murine models. In
addition, for HC (7, 8) as well as other pathogens,
TNF- has also been shown to have an essential effector role for
control of infection. The ordered sequence of these cytokine responses
has been modeled for many of the aforementioned intracellular
infections. First, macrophages and/or dendritic cells are infected,
process Ag, and then release cytokines, which include IL-12 and
TNF-. IL-12 can then induce production of IFN- from cells
expressing a functional IL-12 receptor, such as NK cells, leading to
the release of IFN-. This early sequence of events characterizes
part of the innate immune response. Subsequently, cells of the acquired
immune response (CD4+ and
CD8+ T cells) become activated and provide
additional immunity sufficient to substantially eradicate the infection
and maintain immune memory.
The importance of T cells in HC infection has been clearly demonstrated
by several findings. First, nude or SCID mice are more susceptible to
systemic infection with HC (9, 10). In addition, depletion
of 
T cells in naive mice leads to increased fungal burden and
accelerated mortality in both primary and secondary infection
(8). Furthermore, studies have delineated the role of
specific types of T cells following pulmonary or systemic HC infection.
With regard to systemic infection, depletion of
CD4+ T cells in naive mice at the time of
infection resulted in accelerated mortality (8, 11). By
contrast, systemic infection either of naive mice depleted of
CD8+ T cells at the time of infection or of
2-microglobulin-deficient
(2m-/-) mice did not
result in a fatal outcome. However, these mice did have an increased
fungal burden when compared with controls (12). In the
pulmonary model of HC infection, naive mice depleted of
CD4+ T cells had a marked decrease in production
of IFN- correlating with the accelerated mortality in these mice
(8). In this same study, mice treated with anti-CD8
had impaired clearance of HC; however, production of IFN- was not
appreciably changed compared with that of control mice. These data
suggest that CD8+ T cells could have a role in
controlling primary pulmonary infection independent of IFN-. This is
consistent with our previous report showing that, following secondary
infection via the i.v. route, control of fungal growth can be sustained
in the absence of IFN- but is dependent on either
CD4+ or CD8+ T cells
(7). Together, these data clearly demonstrate that an
IFN--independent mechanism exists for control of HC infection and is
dependent on CD4+ or CD8+ T
cells.
The focus of this study was to determine cytokine-dependent and
-independent mechanisms by which T cells mediate immunity to HC
infection. In this report, we show that perforin has an essential role
in primary immunity to systemic HC infection. In addition,
CD8+ T cells are shown to mediate control of HC
infection in a perforin-independent manner. Data are also presented
that suggest that this latter pathway is mediated by IFN-. Together,
these data provide new evidence for a critical role of perforin in
primary immunity to HC, furthering our understanding of the
multifactorial manner in which primary immunity to HC is controlled by
T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Perforin-deficient knockout (PfKO) mice derived using a C57BL/6
embryonic stem cell line were purchased from The Jackson Laboratory
(Bar Harbor, ME). In the experiments, C57BL/6 mice obtained from either
The Jackson Laboratory or the National Cancer Institute were used with
identical results. IFN--/-, MHC class
II-deficient, and
2m-/- mice that were
homozygous on the C57BL/6 background were purchased from Taconic Farms
(Germantown, NY). All mice were kept in the National Institute of
Allergy and Infectious Diseases Animal Care Facility under
pathogen-free conditions. Mice used were between 6 and 10 wk of age.
For primary infection, mice were inoculated i.v. in 0.5-ml sterile PBS
with either a lethal (6 x 105) or sublethal
(6 x 104) dose of HC yeast cells. In
experiments studying secondary immunity, mice were initially immunized
i.v. with a sublethal dose (6 x 104 or
1 x 104) of HC and then challenged with a
lethal dose (6 x 105) of HC 3 wk later.
Media
HBSS and PBS (BioFluids, Rockville, MD) were used as wash media. Complete medium was used for culturing spleen cells: RPMI 1640 (BioFluids) supplemented with 10% FCS (BioFluids), penicillin (100 U/ml), streptomycin (100 µg/ml), L-glutamine (2 mM), sodium pyruvate (1 mM), and 2-ME (0.05 mM).
Preparation and quantitation of HC
Yeast-phase HC (strain GS-57) was used for infection in all experiments as previously described (4). Quantitation of HC was performed as previously described (4). Briefly, three individual mice infected with HC and/or treated with different Abs were sacrificed at various times postinfection. Spleens were then homogenized in a sterile mortar using PBS to prepare a 1:10 weight:volume suspension. The serial 10-fold dilutions in PBS were plated in duplicate at 0.05 ml/plate on brain-heart infusion (BHI)-supplemented albumin growth factor chloramphenicol medium and incubated for 7 days at 30°C. Colonies were enumerated and the counts recorded as CFU. BHI-supplemented albumin growth factor chloramphenicol agar plates contained 37 g/L BHI, 15 g/L Bacto-Agar (Difco Laboratories, Detroit, MI), 0.1% BSA (Sigma, St. Louis, MO), 0.01% chloramphenicol, and 1% (v/v) growth factor prepared by Dr. R. P. Tewari (Department of Medical Microbiology and Immunology, Southern Illinois Medical School, Springfield, IL). Statistical analysis is described below.
In vivo treatment of mice
Purified rat anti-mouse IFN- mAb (XMG1.2),
anti-TNF- (XT22), and anti-CD8 (2.43) were used to
neutralize IFN-, neutralize TNF-, and deplete
CD8+ T cells, respectively. Mice were treated
with a single injection of anti-IFN- (1 mg) or anti-TNF-
(1 mg) i.p. at the time of primary infection. For T cell depletion,
anti-CD8 Ab were injected 3 days before, at the time of, and 3 days
postinfection. This treatment resulted in a >95% depletion of
CD8+ T cells from spleens at 1 wk after infection
as assessed by FACS analysis (BD Biosciences, San Jose, CA).
Adoptive transfer experiment
Donor cells were harvested from spleens of PfKO mice or C57BL/6
mice that had been infected with a sublethal dose of HC yeast cells
(1 x 104) 3 wk before transfer.
CD8+ T cells were then isolated by positive
selection using MACS CD8a (Lyt-2) beads from Miltenyi Biotec (Bergisch
Gladbach, Germany). The purity of CD8+ T cells
was >90% as assessed by FACS analysis. A total of 3 x
106 CD8+ T cells in 0.5 ml
PBS were adoptively transferred i.v. into naive
IFN--/- mice. After 2 h,
IFN--/- mice were infected with 3 x
104 HC yeast cells.
Measurement of NK cell functional activity
51Cr release assays were performed as previously described (13). Briefly, yeast artificial chromosome (YAC)-1 lymphoma target cells were incubated for 1 h with 500 µCi of Na51CrO4 (Amersham, Arlington Heights, IL), followed by extensive washing twice in HBSS medium. The target cells were resuspended and added in place of effector cells in 96-well round plates. The effector cells were obtained at various time points from the spleens of three individual normal C57BL/6 or PfKO mice infected with HC. As a control, spleen cells from uninfected normal C57BL/6 and PfKO mice were also used in parallel. E:T ratios of 100:1, 50:1, 25:1, 12.5:1, and 6.25:1 were used in a total volume of 150 µl. Plates were incubated for 4 h at 37°C in a 5% CO2 incubator. Chromium release into the supernatants was determined with a gamma counter (Beckman Instruments, Palo Alto, CA). Specific 51Cr release was determined as follows: maximum chromium release and spontaneous release were calculated from wells incubated with 20 µl of 10% SDS (Sigma, St. Louis, MO) or medium alone, respectively. The percentage of specific release of 51Cr was calculated by the formula: % = [(experimental release - spontaneous release)/(maximum release - spontaneous release)] x 100%.
Statistics
For quantitation of fungal burden, statistical evaluation of differences between the means of experimental groups was done by ANOVA and with a multiple Student’s t test. The log rank was used for statistical analysis of mortality. A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous work has established a central role for IL-12-dependent
production of IFN- in primary immunity against HC (4, 5), similar to many other intracellular infections. In addition,
it has been shown that IFN--independent cytolytic mechanisms can
also mediate a protective response against other intracellular
pathogens such as L. monocytogenes (14). Our
goal was to elucidate additional mechanisms of immunity to HC, focusing
on the role of cytokine-independent, cytolytic pathways. In this
regard, the first experiments established the role of
CD4+ and CD8+ T cells in a
systemic model of disseminated histoplasmosis. As shown in Fig. 1
, MHC class
II-/- or
2m-/- mice had
accelerated mortality compared with infected wild-type mice. The
accelerated mortality correlated with increased fungal burden from
spleens of these mice taken 6 days postinfection (data not shown). In
addition, similar data were obtained from mice treated with
anti-CD4, anti-CD8, or both. Together, these data suggest a
role for both CD4+ and CD8+
T cells in primary systemic infection by HC.
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As an extension to the data shown above, the role of
CD4+ and CD8+ T cells
following secondary infection was also assessed using MHC class II- and
2m-deficient mice, respectively (Fig. 2). In these experiments, C57BL/6, MHC
class II-, or 2m-deficient mice were initially
infected with a sublethal dose of HC (6 x
104) and then reinfected with a lethal dose
(6 x 105) 3 wk later. It should be noted
that at the time of reinfection similar amounts of HC
(
103 CFU) were detected from the spleens from
C57BL/6, MHC class II-/-, or
2m-/- mice (data not
shown). As shown in Fig. 2, MHC class II-/- or
2m-/- mice initially
infected with a sublethal dose of HC survived secondary infection
following a lethal challenge. In similar experiments, mice depleted of
either CD4+ or CD8+ T cells
at the time of secondary infection also survived a lethal challenge
with HC (data not shown). These data suggest that following primary
infection either CD4+ or
CD8+ T cells alone may be sufficient to control a
secondary challenge.
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Immune effector mechanisms by which CD4+ and
CD8+ T cells could exert control of HC are
through the production of cytokines such as IFN- and TNF- and/or
through a cytolytic mechanism. Because we were interested in exploring
noncytokine-dependent pathways for immunity, the role of perforin in
immunity to HC infection was assessed using PfKO mice. As shown in Fig. 3A, in data combined from
three independent experiments, PfKO mice infected with a lethal dose of
HC (6 x 105) had accelerated mortality
(13.5 ± 2.1 days) and increased fungal burden at both 7 and 14
days postinfection compared with wild-type mice (18.1 ± 3.6 days)
(p < 0.01). Remarkably, all the PfKO mice
succumbed, even following a sublethal (6 x
104) primary challenge (27.6 ± 1.8 days),
which again correlated with increased fungal burden compared with the
control mice (p < 0.001). Thus, in addition to
the essential role for cytokines, these surprising data highlight a
critical role for perforin in mediating primary immunity to HC.
Finally, the role of perforin in secondary immunity was also assessed.
For these experiments, mice were initially infected with a very low
dose of HC (1 x 104) and then rechallenged
with a lethal dose 3 wk later. As shown in Fig. 3B, perforin
was not required for protective immunity following secondary challenge
with a normally lethal dose of HC. However, it should be noted that
PfKO mice did have an 4-fold increase in fungal burden when assessed
14 days postreinfection compared with C57BL/6 mice. Together, these
data are consistent with our previous reports showing that many of the
factors (e.g., cytokines, neutrophils, NO) required for primary
immunity may not be essential to mediate protection following secondary
challenge (7).
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The findings in the previous figures showing that both
CD8+ T cells and perforin have critical roles in
mediating protective immunity in primary infection to HC raise the
question of whether CD8+ T cells are mediating
their effect exclusively through perforin and/or through the production
of cytokines such as IFN- and TNF-. To further delineate the
respective roles for the aforementioned factors, PfKO mice were
depleted of CD8+ T cells at the time of
infection. In addition, PfKO mice were treated with Abs against IFN-
or TNF- at the time of infection to assess the role of cytokines in
the absence of a major cytolytic mechanism. Similar to the results
shown above, PfKO mice had accelerated mortality (15.0 ± 1.5
days) compared with wild-type mice (21.8 ± 2.9 days)
(p < 0.001) (Fig. 4A). In addition, PfKO mice
depleted of CD8+ T cells succumbed even earlier
to infection (10.0 ± 0.4 days) compared with PfKO mice not
depleted of CD8+ T cells. These latter data
suggest that CD8+ T cells have a role in primary
immunity independent of perforin. Furthermore, PfKO mice depleted of
IFN- (Fig. 4A) (8.8 ± 1.0 days) or TNF- (Fig. 4B) (7.5 ± 0.6 days) had accelerated mortality when
compared with noncytokine-depleted PfKO mice (p
< 0.001). These latter data suggest that both IFN- and TNF- have
a role in mediating immunity in the absence of perforin. As a biologic
correlate to the mortality data, the fungal burden was assessed from
spleen cells of all the groups at 7 and 15 days postinfection.
Depletion of CD8+ T cells caused a 2- to 3-fold
increase in fungal burden from spleen cells of PfKO mice when compared
with the CFU obtained from non-CD8+ T
cell-depleted PfKO mice (p < 0.001) (Table I). Furthermore, depletion of IFN- or
TNF- in PfKO mice caused 5- and 17-fold increases in the
amount of HC, respectively, compared with PfKO mice. Thus, primary
protection against HC appears to be mediated through a variety of
pathways that includes CD8+ T cells, perforin,
IFN-, and TNF-.
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-/- mice
The previous findings that depletion of CD8+
T cells in PfKO mice causes increased fungal burden and accelerated
mortality suggest that production of IFN- and/or TNF- by
CD8+ T cells may mediate control of infection. To
directly determine whether CD8+ T cells from PfKO
mice have effector function in vivo, highly purified
CD8+ cells from previously infected PfKO and
wild-type C57BL/6 mice were adoptively transferred into
IFN--/- mice. These mice were then
challenged with HC. As shown in Fig. 5, IFN--/- mice succumbed (10.4 ± 0.5
days) to a sublethal infection with HC. Adoptive transfer of
CD8+ T cells isolated from infected PfKO mice
resulted in enhanced survival (17.3 ± 1.8 days)
(p < 0.001) and reduced fungal burden
(4-fold decrease) compared with the control-infected
IFN--/- mice (p <
0.001). Moreover, adoptive transfer of CD8+ T
cells from wild-type C57BL/6 mice resulted in longer survival
(23.8 ± 2.7 days) (p < 0.001) and a more
striking decrease (20-fold) in fungal burden compared with that of
mice receiving CD8+ T cells from PfKO mice
(p < 0.001). These data provide clear evidence
that CD8+ T cells from PfKO mice can have
effector function in vivo, as assessed by survival and reduction in
fungal burden. Moreover, this effector function could be mediated by
IFN-.
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Because perforin is present in both CD8+ T
cells and NK cells, it was of interest to determine whether
CD8+ or NK cells from PfKO mice could mediate any
killing of target cells in vitro. To date, we have not been successful
in developing an assay for CD8+ CTL activity in
vitro; however, we were able to assess NK cytolytic activity using
YAC-1 cells as targets. As shown in Fig. 6A, lysis of YAC-1 cells by
total spleen cells from C57BL/6 mice was substantially enhanced from
infected spleen cells of C57BL/6 but not PfKO mice when assessed 3 days
postinfection. Similar data were seen in a separate experiment (Fig. 6B). Moreover, in this same experiment, there was
essentially no cytolytic activity detected from either infected C57BL/6
or PfKO mice when assessed 6 days postinfection (Fig. 6C).
Thus, these data suggest that early NK cytolytic activity mediated by
perforin (15, 16) may be important in the initial control
of fungal growth.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF- work in concert with
cytolytic mechanisms (i.e., perforin) to provide protective immunity
against primary infection by a pathogenic fungus. The role of perforin in primary and secondary immunity to HC
The most striking finding of our studies reported here is the importance of perforin in mediating primary immunity to HC. The importance of perforin was highlighted by the observation that PfKO mice readily succumbed in response to a sublethal infection. With regard to the role of perforin in immune protection against other infections, previous work has demonstrated that perforin is essential for protection against certain viral (16, 17) and bacterial (18) infections. By contrast, although perforin appears to have some role in immunity against other intracellular infections such as Mycobacterium tuberculosis (19) and Toxoplasma gondii (20), it is not essential for protective immunity. Thus, because there is a commonality in the requirement for type 1 immune responses for protective immunity against M. tuberculosis, T. gondii, and HC, the requirement for perforin in primary HC infection is unique. Once primary immunity is established against HC, perforin does not appear to be required to sustain protection following secondary challenge.
There are several mechanisms by which perforin could mediate its
effects in HC infection. First would be a direct role in which perforin
released by CD8+ T cells causes lysis of an
infected target cell. It is also possible that perforin from NK cells
has a similar direct role in mediating intracellular killing early in
infection. As noted in Fig. 6
, there was essentially no lysis of YAC-1
target cells in vitro using spleen cells from PfKO mice following
infection. By contrast, lysis of YAC-1 cells was detected from spleen
cells of wild-type mice at 3 days but not at 6 days postinfection.
These data suggest that if NK cell cytolysis is important in immunity
against HC, it would likely be early after infection and be mediated by
perforin (15).
Perforin-dependent and -independent pathways of immunity to HC
As noted above, there are at least two major pathways by which
intracellular infections are eliminated. One pathway is via cytokines
such as IFN- and TNF-, and the other is through a direct
cytolytic pathway by perforin- or Fas-mediated lysis. In this regard,
there has been a substantial amount of work in delineating the
respective roles of cytokines and cytolytic mechanisms in the
Listeria mouse model of infection. In this model, initial
studies showed that in adoptive transfer experiments, protective
immunity by CD8+ T cells from PfKO mice was
substantially less than from wild-type mice following
Listeria challenge (18). These data established
an important role for perforin in this infection. Interestingly, in a
subsequent study by Harty and Bevan, CD8+ T cell
immunity against L. monocytogenes could be sustained in the
absence of IFN- (14). Moreover, these data were
substantiated in a separate report showing that
CD8+ but not CD4+ T cells
from IFN--deficient mice could clear chronic infection when
transferred into SCID mice (21). Together, these data
clearly established a CD8+ T cell-dependent,
IFN--independent mechanism for protection against
Listeria. Several additional studies showed that in the
absence of both perforin and IFN-, TNF- had a critical role in
mediating immunity in the spleen following infection (22, 23).
In the studies reported here, it was of interest that depletion of
CD8+ T cells in infected PfKO mice resulted in
increased fungal burden and accelerated mortality when compared with
infected PfKO mice only. These data suggest that
CD8+ T cells could mediate some immunity against
HC in the absence of perforin. Furthermore, CD8+
T cells from PfKO mice did provide some immunity when adoptively
transferred into IFN--/- mice. Thus, these
data suggest that there is a perforin-independent mechanism of immunity
that is likely due to low levels of IFN- and/or TNF-.
A model for mechanisms regulating primary and secondary immunity to disseminated histoplasmosis
Based on previous data in addition to those reported here, the
factors necessary for primary immunity to pulmonary or systemic HC
infection require a coordinated response mediated by a multitude of
factors. By contrast, for secondary immunity to HC there is redundancy
in the requirements for protection such that immunity can be sustained
in the absence of factors required for primary infection. With regard
to the role of T cells in primary immunity, it is clear that
CD4+ T cells are essential for primary immunity
to HC infection. Furthermore, depletion of CD4+ T
cells is correlated with a marked reduction in production of IFN-
(8). Thus, CD4+ T cell production of
IFN- appears to be the major mechanism by which they mediate their
effect. For secondary infection, CD4+ T cells are
not required for protective immunity; however, in a study in which mice
were treated with a drug to control primary infection,
IFN--/- mice were shown to survive and clear
infection following a secondary lethal challenge (7).
Furthermore, depletion of CD4+ T cells or TNF-
in these mice caused accelerated mortality and a striking increase in
fungal burden. Thus, these data are consistent with a critical role for
TNF- in secondary infection that is independent of IFN- (7, 24) and suggest that CD4+ T cells may be a
source for this TNF-, or may be required to initiate TNF-
expression by some other cell type. CD8+ T cells
also appear to have an important role in controlling fungal growth in
primary immunity against HC. As shown here, one mechanism by which
CD8+ T cells mediate their effect is through
perforin. Moreover, in the absence of perforin, we show here that
CD8+ T cells do have an effector role in primary
infection that is likely mediated through IFN- and/or TNF-. For
secondary immunity, CD8+ T cells or perforin are
not required. Our previous data showed that in the absence of IFN-,
depletion of CD8+ T cells resulted in accelerated
mortality following secondary infection. These data suggest that
perforin or TNF- from CD8+ T cells may have a
role in secondary immunity in the absence of
IFN--/-, which is similar to data obtained
in the Listeria mouse model (25). Overall,
these data extend previous work in elucidating the cellular mechanisms
by which immunity is achieved following infection by HC.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: HC, Histoplasma capsulatum; 2m, 2-microglobulin; PfKO, perforin-deficient knockout; BHI, brain-heart infusion; YAC, yeast artificial chromosome.
Received for publication August 2, 2000. Accepted for publication November 13, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Immunol. 152:1883.[Abstract]
. J. Immunol. 155:785.[Abstract]
plays a critical role in maintaining secondary immunity in the absence of IFN-. J. Immunol. 160:1359., mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J. Immunol. 157:4045.[Abstract]
. Immunity 3:109.[Medline]
but requires TNF-. J. Immunol. 160:898.. J. Immunol. 164:6444., is essential for acquired resistance to Listeria monocytogenes during a secondary infection in mice. Immunology 86:256.[Medline]
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,
Significantly different (p < 0.001) compared with
IFN-