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in IL-12-Deficient Mice During Toxoplasma gondii Infection1
Departments of
*
Physiology,
Microbiology, and
Medicine, Dartmouth Medical School, Lebanon, NH 03756
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in regulating the host CD8+ T
cell response during microbial infection has not been delineated. Mice
deficient for the p40 chain of the IL-12 heterodimer have impaired
IFN- production and are susceptible to infection with the
intracellular parasite Toxoplasma gondii. The
administration of exogenous IFN- to parasite-infected
p40-/- mice increases survival and up-regulates the
depressed CD8+ T cell response following infection.
CD8+ T cells isolated from cytokine-treated
p40-/- mice exhibit an increase in both precursor CTL
frequency and IFN- production compared with untreated controls. The
enhancement of the CD8+ T cell response is independent of
CD4+ T cell help. These CD8+ T cells induce
protective immunity against a lethal challenge when adoptively
transferred into naive p40-/- and
IFN--/- mice. These observations indicate that IFN-
can regulate the CD8+ T cell response during T.
gondii infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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has been shown to provide a wide range of critical regulatory functions
in the immune response. The primary mechanism by which IFN- protects
against microbial infection is believed to be via macrophage activation
(1). Synergism of IFN- with a second effector molecule, such as
TNF-
, stimulates the production of nitric oxide
(NO)3 (2). The inhibitory effect
of NO against both tumor cells and microbial pathogens, including
Toxoplasma gondii, is well documented (3, 4, 5). However,
recent studies indicate that IFN- can induce protection in the
infected host by an NO-independent mechanism (6). An alternative
mechanism would be the induction of Ag-specific CD8+ CTLs.
A potential role for IFN- in the induction of CD8+ T
cells has been suggested (7). CD8+ T cells are known to
have important effector functions in host immunity against
intracellular pathogens (8, 9). The stimulation of CD8+ T
cells is regulated via MHC class I expression on APCs that can be
up-regulated by IFN- (10). Previous studies (11, 12) have
demonstrated that IFN- and CD8+ T cells are essential
for the induction of protective immunity with the temperature-sensitive
mutant (ts-4) of T. gondii, first isolated by Waldeland et
al. (13). In other microbial infections, it has been demonstrated that
treating lymphocytic choriomeningitis virus (LCMV)-infected mice with
anti-IFN- Ab can down-regulate the CD8+ T cell
response against the virus (14). However, a direct association between
the expression of IFN- and the induction of CD8+ T cell
immunity in response to a microbial infection has not been reported.
IFN- is crucial for resistance during both acute and chronic
infection with T. gondii (15, 16). Deletion of the p40 chain
of IL-12 heterodimer in mice results in diminished IFN- production
(17). In this study, we used p40-/- mice to evaluate the
role of IFN- in the induction and maintenance of CD8+ T
cells in response to infection with T. gondii.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The temperature-sensitive mutant strain of T. gondii, ts-4 (kindly provided by Dr. Elmer Pfefferkorn, Dartmouth Medical School), was used for vaccination of animals. The strain is maintained by continuous passage in human fibroblasts. Mice were challenged with the 76K strain of T. gondii, which was provided by Dr. Daniel Bout (University of Tours, Tours, France). This strain is maintained by the continuous oral passage of cysts as described previously (18). Cysts were isolated from infected tissue, enumerated, and used to orally infect the animals. A challenge dose of 20 cysts was used unless otherwise noted.
Mice
A breeding pair of p40-/- mice on a C57BL/6
background, were kindly provided by Dr. Maurice Gately (Hoffman-La
Roche, Nutley, NJ). As reported previously, these mice are unable to
produce IL-12 (17). IFN--/- mice on a similar genetic
background were obtained from the Jackson Laboratory (Bar Harbor, ME).
Age and sex matched parental C57BL/6 mice were used for wild-type (wt)
controls. All of the mice used were female and were 6–8 wk of age.
Vaccination and challenge
Vaccinations of p40-/- and wt C57BL/6 mice were conducted by injecting the animals i.p. with 1 x 103 ts-4 parasites. After 3 wk, the mice were boosted a second time with 5 x 104 parasites of the same strain. Vaccinated animals were challenged later with 20 cysts of the 76K strain of T. gondii via oral route.
In vivo cytokine and T cell depletion
For IFN- depletion, mice were treated with 3 mg of rat
anti-mouse IFN- (XMG6; American Type Culture Collection (ATCC),
Manassas, Va) weekly. Control mice received equal quantities of rat IgG
(Sigma). Ab depletion of the vaccinated mice began 3 days before
challenge and continued weekly thereafter. To deplete CD8+
T cells, mice received 1 mg of anti-CD8 (clone 2.43; ATCC) for 3
days at the beginning and on every third day thereafter.
CD4+ depletion of mice was performed by the administration
of rat anti-mouse GK1.5 (ATCC) at a dose of 0.5 mg/day for 3
consecutive days, continuing every third day thereafter. The Ab
treatment resulted in >95% depletion of the phenotype as determined
by FACS analysis.
In vivo cytokine administration
Mice were treated with 2500 U of murine IFN- (Genzyme,
Cambridge, MA) on alternate days beginning 2 wk after the second
immunizing dose and continuing for 
10 days. This dose of IFN- has
been shown previously to significantly enhance protection against acute
T. gondii infection (19).
IFN- assay
IFN- assays of T cell subtypes from the immunized animals
were performed. At 1 mo after the last vaccinating dose, the CD4 and
CD8+ T cells from the splenocytes were isolated by magnetic
separation as described previously (20), with a resulting purity of
>95% as determined by FACS analysis. Purified cells were extensively
washed with medium and stimulated in vitro with Toxoplasma
lysate Ag (TLA) and irradiated feeder cells. Cells were harvested after
incubation for 72 h, and supernatants were collected and assayed
for IFN- production by cytokine ELISA (Genzyme).
Cytotoxicity assays
Cell-mediated cytotoxicity was determined using a standard microcytotoxicity assay (21). The cytolytic activity of the T cells was quantitated by determining the precursor CTL (pCTL) frequency of the immunized mice using limiting dilution assays (LDAs). CD8+ T cells from the vaccinated splenocytes were isolated by magnetic separation as described above. Purified cells were cultured by limiting dilution in 96-well, round-bottom plates. Cells were grown in RPMI 1640 medium containing appropriate growth factors including IL-2, irradiated parasites, and feeder cells. Dilution of cells ranged between 100 and 25,000 cells/well. Wells containing only irradiated parasites and feeder cells, without effector cells, served as controls. After 1 wk, the cells were harvested and incubated with 51Cr-labeled parasite-infected and uninfected macrophages. Macrophages were collected and labeled as described elsewhere (20). pCTL frequency was calculated according to a standard formula (22).
Adoptive transfer of CD8+ T cells
p40-/- mice were vaccinated with ts-4 parasites as
mentioned and subsequently administered IFN- as described
previously. Mice were splenectomized at 5 days after the completion of
cytokine administration, and spleen cells from immunized and nonimmune
controls were isolated and collected. CD8+ T cells were
separated and purified. A total of 1 x 107
CD8+ T cells were adoptively transferred to naive p40 and
IFN- knockout (KO) mice via i.v. tail vein inoculation. At 24 h
after the adoptive transfer of immune cells, mice were challenged with
20 cysts of the 76K strain.
Statistical analysis
Statistical analysis of the data was performed using two sampled Student’s t tests (23).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IFN--/- mice, p40-/- mice, and
parental C57BL/6 mice were infected with varying numbers (250–1
x 106) of ts-4 strain tachyzoites.
IFN--/- mice were highly susceptible, with all mice
dying with an infective dose of 250 tachyzoites (data not shown). The
wt mice could tolerate the highest parasite challenge without evidence
of morbidity (as determined by body weight change and ruffled fur) or
mortality (data not shown). In comparison with wt animals,
p40-/- mice were more susceptible to a significantly
lower dose of parasites (Fig. 1
). At
doses of >1 x 103 tachyzoites, all
p40-/- mice succumbed to infection. Vaccination with
1 x 103 ts-4 tachyzoites resulted in 70% of the
p40-/- mice being able to survive challenge. At 3 wk
postinfection, the serum anti-Toxoplasma IgG titer was
>1200 in both p40-/- survivors and parental control mice
(data not shown).
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Vaccination of p40-/- mice increased resistance to
subsequent challenge with ts-4 tachyzoites (Fig. 2). Mice vaccinated with 1 x
103 parasites could tolerate a challenge dose of 5 x
104 tachyzoites. Below a vaccination dose of 1 x
103, the mice were not protected when challenged with
5 x 104 tachyzoites (data not shown). Unvaccinated
controls died by day 14 postchallenge. Protection in the vaccinated
mice was dependent upon IFN-, as treatment with neutralizing Ab
increased susceptibility (Fig. 2).
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A), although the vaccinated
and orally challenged mice began to die by day 26. The increased
survival time of p40-/- vaccinated mice could be reduced
by the deletion of either IFN- or CD8+ T cells. In
comparison, all of the vaccinated parental strain mice survived the
lethal challenge with the 76K strain parasites, whereas 50% of the
nonvaccinated parental mice succumbed to infection (Fig. 3B).
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was administered to p40-/- mice to
determine its effect on mortality. Mice were immunized with the ts-4
strain and subsequently challenged with the 76K strain of T.
gondii, as mentioned above. A group of vaccinated animals was
treated exogenously with IFN- starting 2 wk after the second
immunization. IFN- treatment reversed the death of the
p40-/- animals, and these animals continued to survive
until termination of the experiment, unlike the saline-treated animals,
which succumbed to infection as observed earlier (Fig. 4).
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The production of IFN- by the CD8+ T cells from
ts-4-vaccinated p40-/- mice in response to antigenic
restimulation was evaluated. Supernatants obtained from
CD8+ T cell cultures following Ag exposure were analyzed
for IFN- production. As shown Table I,
CD8+ T cells from ts-4-vaccinated p40-/- mice
produced significantly less IFN- than CD8+ T cells from
parental mice (p = 0.003). Treating
p40-/- mice with exogenous IFN- resulted in a
significant increase in the production of IFN- by the
CD8+ T cells (p < 0.0001). Similar
data were obtained upon repeated experiments. Exogenous IFN-
treatment of parental wt mice did not cause any significant changes in
the IFN- profile of the CD8+ T cells of these mice.
Purified CD8+ T cells from uninfected control mice treated
with exogenous cytokine secreted very little IFN- in response to
antigenic stimulation (data not shown).
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treatment on
the cytokine production by CD4+ T cells from infected
p40-/- mice. As shown in Table II, similar to CD8+ T cells,
cytokine treatment results in a significant increase in IFN-
production by the CD4+ T cells from p40-/-
animals (p < 0.001) However, an in vivo
depletion of CD4+ T cells had no effect on the levels of
IFN- released by CD8+ T cells.
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The Ag-specific CD8+ T cells elicited in response to
ts-4 vaccination are cytotoxic against Toxoplasma-infected
targets. To estimate the frequency of Ag-specific CD8+ T
cells, a pCTL assay was performed. At 1 mo following ts-4 vaccination,
the pCTL frequency of p40-/- mice was 1/126,000 cells,
compared with 1/4,100 in the parental control group (Fig. 5A). Administration of
exogenous IFN- to the ts-4-vaccinated p40-/- mice
increased the pCTL frequency to 1/9,800, which is within the range of
variability of the immune CD8+ T cell population of
parental wt mice (24). The treatment of vaccinated wt C57BL/6 mice with
IFN- had no significant effect on the pCTL frequency of the
CD8+ T cell population of these mice (data not shown). The
increased pCTL frequency in the IFN- treated p40-/-
mice was independent of CD4+ T cell population. In vivo
depletion of this T cell subtype did not alter the frequency of
IFN--treated p40-/- animals (Fig. 5B). LDA
showed no killing of control uninfected targets.
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CD8+ T cells from the ts-4-vaccinated
p40-/- mice were assayed for their ability to protect
naive p40-/- mice against a parasite challenge. Equal
numbers of CD8+ T cells isolated from both ts-4 vaccinated
and control mice were adoptively transferred into naive recipient
p40-/- mice and were challenged perorally after 24 h
with 20 cysts of the 76K strain of T. gondii. All recipient
mice immunized with CD8+ T cells from either the ts-4
vaccinated or control mice died postchallenge, although the mice
receiving the Ag-primed cells did survive several days longer (Fig. 6A). In comparison, all mice
receiving CD8+ T cells from IFN--treated,
ts-4-vaccinated mice survived the infection. These mice had no clinical
evidence of illness, including ruffled fur, weight loss, or huddling.
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gene. Purified CD8+ T cells were adoptively transferred to
naive IFN--/- mice and challenged the following day as
described above. IFN- KO mice immunized with CD8+ T
cells from vaccinated and IFN--treated animals survived the
infection, similar to p40-/- mice (Fig. 6
B).
An in vivo depletion CD4+ T cells from donor mice before
IFN- treatment had no effect on the ability of CD8+
cells to protect the recipient mice. On the contrary, CD8+
T cells from mice vaccinated with ts-4 alone were unable to protect
IFN--/- mice against a Toxoplasma
infection. All animals succumbed to challenge by day 8 postchallenge
(Fig. 6B), unlike p40-/- recipients, which
were able to survive the infection for 21 days (Fig. 6A). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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following ts-4 infection is produced in both an
IL-12-dependent and -independent fashion. However, based upon our
observations, an IL-12-dependent pathway predominates as the source of
IFN- production in ts-4-infected animals during acute infection.
p40-/- animals survive only low-dose initial challenge,
and IFN- production in these mutant mice in response to infection is
severely impaired.
One of the major consequences of lowered IFN- levels in
p40-/- mice was the down-regulated CD8+ T
cell response against the parasite. The observations presented here
demonstrate an important and perhaps essential role for IFN- in the
regulation of CD8+ T cell immunity in response to microbial
infection. The interaction between CD8+ T cells and IFN-
during intracellular infections is not well understood. Earlier reports
with viral systems have suggested a role for IFN- in the induction
of CD8+ T cell immunity (7, 14), because a neutralization
of endogenous IFN- results in the reduction of CD8+ T
cell numbers and CTL activity. However, other studies have shown the
development of a normal CTL response in IFN--/- mice
(28, 29). A possible explanation for these differences could be the
redundancy in KO mice that has been described previously in other
systems (30, 31). Alternatively, CTL induction in the host may be
dependent upon the pathogen involved. This possibility is supported by
the observation of Leist et al. (32), demonstrating that animals
treated with anti-IFN- Ab develop a normal CTL response against
vaccinia virus and vesicular stomatitis virus but have a reduced CTL
response against LCMV infection.
The present study provides an in-depth analysis of the role of IFN-
in the regulation of CD8+ T cell immunity during
Toxoplasma infection. We have demonstrated the importance of
IFN- in the generation of a robust memory CD8+ T cell
response. In the absence of optimal IFN- levels, the frequency of
Ag-specific memory CD8+ T cells, as a result of vaccination
with T. gondii, is severely reduced. This reduction in
Ag-specific memory CD8+ T cells results in the increased
susceptibility of the vaccinated host against a challenge infection.
Treatment with exogenous IFN- restores the impaired CD8+
T cell immunity, as measured by increased IFN- production and pCTL
frequency. The CD8+ T cells from the IFN--treated mice,
unlike those from untreated animals, protect the naive animals against
lethal infection. These observations are similar to the studies with
LCMV, for which the immune cells from IFN--/- mice
were unable to clear the persistent infection in a naive host (29).
Based upon earlier observations with T. gondii (12), we
could postulate that the IFN--mediated augmentation of the
CD8+ T cell response is due to increased CD4+ T
cell helper activity. However, this explanation can be discounted, as
the depletion of CD4+ T cells in the IFN--treated
vaccinated mice had no effect on CD8+ T cell function of
these animals. These findings suggest that IFN- directly regulates
the CD8+ T cell response during T. gondii
infection. The observed augmentation of CD8+ T cell
immunity by IFN- may occur as a result of the up-regulation of MHC
class I molecules, thereby enhancing the quality of Ag presentation.
The role of IFN- in class I Ag regulation and processing has been
demonstrated previously (33, 34). Our data, for the first time, provide
direct evidence linking IFN- to the regulation of the
CD8+ T cell response during T. gondii infection.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Imtiaz A. Khan, Department of Medicine, Dartmouth Medical School, HB7506, One Medical Center Drive, Lebanon, NH 03756. E-mail address:
3 Abbreviations used in this paper: NO, nitric oxide; LDA, limiting dilution assay; pCTL, precursor CTL; wt, wild type; KO, knockout; LCMV, lymphocytic choriomeningitis virus; TLA, Toxoplasma lysate Ag.
Received for publication August 24, 1998. Accepted for publication February 4, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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