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T Cells Contribute to Control of Chronic Parasitemia in Plasmodium chabaudi Infections in Mice1
Department of Biology, Imperial College of Science, Technology and Medicine, London, U.K.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells are stimulated and their expansion
coincides with recovery from the acute phase of infection in normal
mice or with chronic infections in B cell-deficient mice (µ-MT). To
determine whether the large T cell pool observed in female B
cell-deficient mice is responsible for controlling the chronic
infection, studies were done using double-knockout mice deficient in
both B and cells (µ-MT x -/-TCR) and in
T cell-depleted µ-MT mice. In both types of T
cell-deficient mice, the early parasitemia following the peak of
infection was exacerbated, and the chronic parasitemia was maintained
at significantly higher levels in the absence of T cells. The
majority of T cells in C57BL/6 and µ-MT mice responding to
infection belonged predominantly to a single family of T cells
with TCR composed of V2V4 chains and which produced IFN-
rather than IL-4. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR increase during a malaria parasite infection in humans and
in rodents 1, 2, 3, 4, 5, 6, 7 . In Plasmodium falciparum infections, the
expanded T cell population comprises cells bearing TCR composed
of V9 chains associated mainly with V2 chains 8, 9, 10 but also
with V1 chains 11, 12 . In response to malaria parasite Ags in
vitro, human V9+ T cells produce proinflammatory
cytokines such as IFN-, IL-1, and TNF-
13 . Since the in vitro
response of T cells to malaria parasite Ag, even among PBMC
collected from nonexposed donors, is large, and the cytokines produced
are those associated with the pathology observed in malaria parasite
infection, it has been proposed that T cells may be pathogenic.
However, there are also data suggesting that human T cells can
inhibit the growth of erythrocytic stage parasites 14 and thus could
play a role in controlling the parasite in vivo.
To determine whether T cells play any role in protective
immunity or in the pathology associated with malaria, mouse models of
the infection have been studied. Despite the differences between mouse
T cell development and migration and those of human 15, 16 , an
increase in the number and proportion of splenic T cells has
also been observed in erythrocytic stage infections with
Plasmodium chabaudi chabaudi, Plasmodium chabaudi adami and
Plasmodium yoelii. 3, 6, 7 . Experiments in gene-targeted
mice lacking ß T cells or T cells, or in mice in which
T cells have been depleted by in vivo treatment with Abs,
clearly demonstrate that T cells are not essential for clearing
blood stage infections 17 . However, they may play some role in the
protective immunity induced by immunization with irradiated sporozoites
18 . Mice lacking B cells due either to targeted disruption of genes
important in B cell development 19 or to treatment with anti-µ
Abs show greatly expanded T cell populations after infection
with erythrocytic stages of P. chabaudi 4, 20 accompanying
the chronic relapsing parasitemia. Depletion of T cells from
P. chabaudi adami-infected B cell-deficient mice results in
an increase in parasitemia, suggesting that T cells exert some
protective effect 21 .
The nature of the TCR(s) expressed by the expanded T cell and
the cytokines produced by these cells during mouse malaria infections
are not known. In other infections or immunization procedures,
production of both Th1-type cytokines such as IFN- and Th2-type
cytokines such as IL-4 by T cells has been described 22, 23, 24, 25 .
In the studies presented here, we show that the T cell
population in normal and µ-MT3 mice infected with
P. chabaudi is composed of cells bearing V2 and V4 TCR
chains and that they produce IFN- rather than IL-4. Double knockout
mice deficient in both B cells and T cells have markedly
elevated parasitemias compared with the µ-MT
single-knockout mice, suggesting that T cells contribute to
control of blood stage parasitemia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female mice homozygous for a targeted mutation of the TCR
gene on a mixed background of mouse strains 129/Sv and C57BL/6
(-/-TCR) 26 and for a targeted mutation in the
transmembrane exon of the IgM µ chain gene (µ-MT)3, 19 backcrossed
for 10 to 12 generations onto C57BL/6 were used in these studies. To
obtain double-knockout mice, F1 progeny of µ-MT x
-/-TCR were mated. Mice homozygous for both mutations
were selected after screening tail DNA by PCR and ELISA as previously
described 19, 26 . Since the double-knockout mice were also on a mixed
background of 129/Sv x C57BL/6, single-knockout mice and wt mice
from the same litters were used as controls. For experiments using only
the backcrossed µ-MT mice, C57BL/6 (Bicester, Harlan, U.K.) were used
as controls. All experiments were performed on 6- to 12-wk-old female
mice. Mice were bred in isolators with sterile bedding, food, and
water, and experimental mice were subsequently maintained in filter
racks under sterile conditions.
Parasites
Mice 6 to 12 wk old were infected i.p. with 105 P. chabaudi chabaudi (AS)-infected erythrocytes as described previously 27, 28 . The course of infection was monitored regularly throughout the experiment by examination of Giemsa-stained blood smears from tail blood.
Antibodies
mAbs specific for mouse TCR- 29 and CD3 30 , labeled
with biotin, fluorescein, or phycoerythrin and the anti-cytokine
mAbs, phycoerythrin-conjugated IL-4 and FITC-conjugated IFN-, as
well as isotype controls were obtained from Pharmingen (San Diego,
CA).
The anti-TCR- mAb used for in vivo depletion experiments was
purified on protein A-Sepharose in our laboratory from the GL3
hybridoma 29 . Purified hamster IgG (Jackson ImmunoResearch Labs, West
Grove, PA) was used as an isotype control antibody.
Flow cytometry analysis
Two- and three-color staining was performed using fluorescein-, phycoerythrin-, and biotin-labeled Abs. The second step reagent for the biotin-labeled Abs was either streptavidin red670 (Sigma, St. Louis, MO) or PerCP (Becton Dickinson, Oxford, U.K.). The Abs were diluted in PBS, pH 7.2, containing 1% BSA, 0.1% NaN3, and 0.05 mM EDTA. Splenic cells (2 x 105) were incubated sequentially with each Ab for 20 min on ice. Cells were washed twice after each Ab labeling. Analysis was carried out on a FACScan (Becton Dickinson) using Becton Dickinson Cell-Quest analysis software. Viable lymphoid cells were selected using forward and 90-degree scatter.
Intracellular analysis of cytokine production
Intracellular cytokine staining was used to determine the cytokine production at the single-cell level as described previously 31 . Cells were resuspended at 106/ml and stimulated with PMA (50 ng/ml) and ionomycin (500 ng/ml). The signals for activation of T cells, achieved by TCR triggering, can be provided in vitro with PMA (activates protein kinase C) and the calcium ionophore ionomycin (allows influx of Ca2+) 32, 33 . PMA and ionomycin were used instead of specific Ag to minimize the variability in kinetics resulting from Ag processing and/or presentation and detects the full potential of cytokine production by T cells 31 . Two hours after stimulation with PMA and ionomycin, brefeldin A was added at 10 µg/ml using a stock of 1 mg/ml in ethanol, and cells were incubated for 2 h. Cells were harvested, washed, and stained for different surface markers using directly conjugated Abs as described in the previous section. At the end of the procedure, cells were washed with PBS without BSA and resuspended in PBS with an equal volume of 4% formaldehyde fixative. After incubation for 20 min at room temperature, cells either were stored in PBS at 4°C for up to 2 days or were immediately stained for cytokines.
For intracellular staining, all reagents were diluted in 1% BSA and
0.5% saponin, and all incubations were carried out at room
temperature. After 10 min in PBS-BSA-saponin, cells were incubated with
anti-IL-4 and anti-IFN- or the respective isotype controls.
These isotype-matched controls were used to set threshold markers on
flow cytometric plots. After 20 min, cells were washed twice with
PBS-BSA-saponin and then with PBS-BSA without saponin. Samples were
analyzed on a FACScan flow cytometer as described above.
In vivo Ab treatment
Anti-TCR Ab and hamster IgG (0.5 mg/mouse) were injected
i.p. into µ-MT mice and C57BL/6 control animals (4–6 mice/group)
every 4 to 5 days, beginning on day 0 of infection. The efficacy of
depletion during the experiment was assessed by flow cytometric
analysis on peripheral blood samples. At the end of the experiment,
mice were sacrificed, and the proportion of T cells within the
splenic lymphocyte population was measured.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cells in the spleens of chronically
infected µ-MT mice
An erythrocytic infection of P. chabaudi chabaudi (AS)
in female µ-MT mice has been described previously 4 and is
characterized by an acute peak of parasitemia similar to that seen in
normal C57BL/6 mice. Parasites are reduced to 0.001% after 
20 days
of infection in µ-MT mice, but in contrast to normal mice, which
clear their infection to subpatent levels thereafter, µ-MT mice
develop a chronic relapsing parasitemia (not shown).
In agreement with our earlier findings, the proportion of T
cells in uninfected µ-MT mice was already higher than that observed
in uninfected C57BL/6 mice 4 . During the first 3 wk of infection,
there was only a minimal further increase in µ-MT mice (Table I
). However, by 35 days of infection, the
proportion of T cells increased fourfold (41% of all
CD3+ T cells) within the spleen and remained at this level
for the period of observation (50 days). By contrast, in control
C57BL/6 mice, the maximum increase in T cells (from 2.4% in
uninfected mice to 10.1%) occurred within 1 wk after infection and was
of similar magnitude during the experimental period.
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T cells (>80%) were composed of V2 and V4 chains
(Table I
).
Cytokines (IFN- and IL-4) produced
by + T cells of µ-MT
mice and C57BL/6 controls during primary infection
with P. chabaudi chabaudi
(AS)
The numbers of splenic T cells from µ-MT and C57BL/6 mice
producing IL-4 and IFN- were assessed during the first 4 wk of a
primary P. chabaudi chabaudi infection using flow cytometry
to detect intracellular cytokines. After PMA and ionomycin stimulation,
the percentages of IFN--producing cells among splenic T cells
from uninfected µ-MT and C57BL/6 mice were 2.45 and 1.72%,
respectively (Fig. 1A). This
increased in infected C57BL/6 mice to a peak of 8.43% 1 week
post-infection and then decreased. By contrast, in µ-MT mice, there
was a continuous increase throughout the 4-wk period of the experiment
and IFN-+ cells comprised 12% of the total T
cell population by 4 wk after infection (Fig. 1A). Similar
results were obtained with cells that had not been stimulated
with PMA and ionomycin, although there were lower numbers of
cytokine-positive cells in each case (Fig. 1B).
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cells producing IL-4 with or without PMA and
ionomycin treatment was low (<2%) for both µ-MT and C57BL/6 mice.
However, even with these low levels it, was apparent that there were
less IL-4-producing cells among cells from µ-MT mice compared
with those from C57BL/6 mice (Fig. 1, C,
D).
Effects of T cell deficiency in
µ-MT mice infected with P.
chabaudi
Double-knockout mice.
Experiments using double-knockout mice were performed on mice of a
mixed genetic background of 129/sv and C57BL/6. In this strain mixture,
female µ-MT mice reduced parasitemias to low levels after 20 days of
infection (0.01 to 0.001% infected erythrocytes) but were unable to
clear the parasites, developing low chronic relapsing parasitemias
between 0.01 and 5.52% (Fig. 2A). Mortality during the
infection was similar to that described previously 4 ; 2 of 8 mice
(25%) died between days 10 and 15. wt littermate control mice reduced
their parasitemias to undetectable levels within 22 days. Female
-/- TCR mice were also able to clear their
parasitemias to subpatent levels (<0.001%) within 22 days of
infection. The peak of parasitemia (8–9 days after infection) was no
higher than that seen in the wt controls; however, parasitemias were
patent 2–3 days longer (Fig. 2B). No deaths occurred in
infected wt or -/-TCR mice.
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-/-TCR)
mice were found to be similar to the µ-MT single-knockout mice in
that the infection was not reduced to subpatent levels. However, the
chronic parasitemia was maintained at higher levels than that observed
in the single µ-MT mice (13.3–29.4%) (Fig. 2A).
Mortality was of a similar magnitude to that observed in µ-MT
single-knockout mice (2 of 8 mice, 25%).
In vivo antibody depletion.
µ-MT mice injected with anti- TCR Ab every 4–5 days for 35
days (Fig. 2C) exhibited higher peak parasitemias than
µ-MT mice injected with the control hamster IgG (31.95%). The
subsequent chronic relapsing parasitemia was in general higher than
that observed in the control treated mice and reached parasitemias of
up to 35% during the 40 days of the experiment.
In agreement with previous reports using T cell-deficient mice
17 , treatment of wt mice with anti- Ab had little effect on
the magnitude of the peak of parasitemia (Fig. 2D). However,
while the wt mice treated with the control hamster IgG reduced their
parasitemias to very low levels at day 15 postinfection, the mice
treated with anti- TCR Ab maintained significant patent
parasitemias until day 22 (Fig. 2D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell population is very marked in B
cell-deficient mice infected with P. chabaudi 3, 4 . In
agreement with previous observations, as many as 40% of the
CD3+ T cells in the spleen expressed TCR after 35
days of infection 3, 4 . Interestingly, the maximum increase in the
numbers of T cells in B cell-deficient mice was observed only
during the later chronic infection, whereas in intact C57BL/6 mice the
increase, albeit of smaller magnitude, was already observed at the time
of acute parasitemia. The reasons for the differences in kinetics are
unclear. The lack of an early increase in T cells in infected
µ-MT mice may be due to the fact that this population is of a size
comparable with those of infected control mice already prior to
infection 4 . The increased numbers seen in the later chronic
infection, although not correlated directly with level of
parasitemia, may be the result of prolonged chronic stimulation and
stress. The T cell population reverts to normal levels only when
parasites are eliminated 4 .
More than 80% of the T cells in infected µ-MT or C57BL/6 mice
at any time of infection had TCR chains made up of V2 and V4
chains. This bias towards particular TCR chains is similar to the
observation in human malaria infections where the predominant T cell
response in vitro or following a P. falciparum infection in
vivo is by T cells bearing V9 and V2 or, less frequently, V1
TCR chains 8, 9, 10, 11, 12 . The TCR gene usage of T cells present in the
lymphoid organs and blood of mice and during infections such as
Listeria and influenza is generally biased towards V1,
V2, V4, and V6 34, 35, 36, 37 , although other TCR chain combinations
have also been observed. T cells bearing the TCR V6/V1
with invariant junctional sequences, normally found in the female
reproductive tract 38, 39 are also found in the liver and spleen
during listeriosis infections 40 suggesting that T cells in
the mouse may not be all tissue specific but can migrate via lymph
nodes and blood. The predominance of one subset of the lymphoid
population of cells in P. chabaudi infections
contrasts with some other infections in the mouse where different
T cells vary in relative frequency at different stages of
infection. In Listeria, the response of T cells
expressing V6.3 or V4 chains may be related to when and where
specific Ags recognized by each individual subset of T cells are
expressed 41, 42 . Similarly, the T cell response induced by
Schistosoma egg Ag differed at different time points
of the infection with V6 chains predominating early in infection and
V4 chains dominating the later response 43 .
Unlike those T cells found in the skin and reproductive tract,
V2 V4 cells belong to a family of T cells that have
diverse TCR due to junctional or N-region diversity 44, 45 .
Therefore, the Ags recognized by these cells in P. chabaudi
infection could be several. T cells are thought to represent a
first line of defense against pathogens and therefore may react either
to promiscuous components shared by different pathogens or to host
proteins induced by infection or released by damaged cells 46, 47 . In
human P. falciparum malaria, the V9V2 cells also
exhibit N-region diversity and appear to recognize phosphorylated
nonpeptidic ligands together with MHC class I- or class I-like
molecules 48 . It has been suggested that two of these ligands,
diphosphoglyceric acid and isophenylpyrophosphate, which are present in
host erythrocytes in large amounts, may be released on schizont rupture
and thus activate T cells 49, 50 . These RBC components,
released after schizont rupture, could be potential candidates for
inducing the dramatic expansion of V2V4 T cells in
chronically infected µ-MT mice.
The majority of female µ-MT mice infected with P.
chabaudi, although unable to clear primary infections, survived
for many weeks with a chronic parasitemia. Since T cell
expansion is significant in this chronic phase, it was important to
know whether these cells contributed to the partial control of
parasitemia observed. In the experiments described here, infection of
µ-MT mice depleted of T cells by in vivo Ab treatment or
double-knockout (µ-MT x -/-TCR) mice resulted
in substantially higher chronic parasitemias compared with untreated or
single-knockout µ-MT mice. The effects of absence of cells
were clearly observed within the first 3 wk of the infection; the
characteristic drop in parasitemia in µ-MT mice after 15 to 20 days
of infection was not observed. Our data show that T cells are
not able to eliminate erythrocytic parasites despite the large increase
in their numbers. However, they play some part in controlling the
infection. These data agree to some extent with previous studies of van
der Heyde et al. In those experiments, B cell-deficient JHD
mice infected with P. chabaudi adami reduced parasitemias to
subpatent levels within the 20-day period of the experiment. Treatment
in vivo with anti- Ab abrogated this clearance, suggesting a
crucial role for cells in resolution of that infection
51 .
Since there are no B cells and no Abs in µ-MT mice, any control of
parasites by T cells must either be by direct recognition of
parasites or infected erythrocytes 14 or by the activation through
cytokines of other cells such as macrophages, which then produce
parasitocidal mediators 52 . It has been established previously that
T cells from spleen and lymph nodes are able to produce both
Th1-type cytokines such as IFN- and as Th2-type cytokines such as
IL-4 22, 25 , depending on the stimulus. In this study, we show that
T cells in µ-MT mice infected with P. chabaudi
produce mainly IFN- and very little IL-4 throughout the infection, a
profile similar to that seen in human T cells responding to
P. falciparum 13, 52 . Further studies of P.
chabaudi infections in µ-MT mice deficient in IFN- production
or depleted of IFN- would establish the importance of this cytokine
in the T cell-dependent partial control of parasitemia.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jean Langhorne, Division of Parasitology, National Institute for Medical Research, The Ridgeway, London NW7 1AA, U.K.
3 Abbreviations used in this paper: µ-MT, B cell-deficient mouse with targeted mutation in the transmembrane exon of the IgM µ chain; wt, wild-type.
Received for publication July 24, 1998. Accepted for publication November 11, 1998.
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W. P. Weidanz, J. R. Kemp, J. M. Batchelder, F. K. Cigel, M. Sandor, and H. C. v. d. Heyde Plasticity of Immune Responses Suppressing Parasitemia During Acute Plasmodium chabaudi Malaria J. Immunol., June 15, 1999; 162(12): 7383 - 7388. [Abstract] [Full Text] [PDF]
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) and C57BL/6 (
) mice infected with erythrocytic
stages of P. chabaudi chabaudi (AS). The cells were taken at
different times after infection and either stimulated or not in vitro
with PMA and ionomycin. Values are the mean percentage of cells
positive for IFN-