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CD8+ T Cells in Experimental Cerebral Malaria1
* Département d’Immunologie, Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unité 567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Hôpital Cochin, Université René Descartes, and
Unité de Parasitologie Biomédicale et Centre National de la Recherche Scientifique Unité de Recherche Associée 1960, Institut Pasteur, Paris, France; and
Department of Cell Biology and Immunology, Faculty of Medicine, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells, which sequester
in the brain at the time when neurological symptoms appear, were
responsible for CM mortality. These observations suggest a mechanism
which unifies disparate observations in humans. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD8+
T cells played an effector role in the neurological symptoms and death
due to CM. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J and BALB/c mice (7–10 wk old) were purchased from Harlan (Gannat, France) while 129/Ola x C57BL/6J (129,B6) wild-type (WT) mice and 129,B6 CD4-deficient mice (12) were obtained from The Jackson Laboratory (Bar Harbor, ME). C57BL/6J back-crossed TAP-1-deficient (13) and CD8-deficient (14) mice were bred in our specific pathogen-free animal facility. All experiments and procedures conformed to the French Ministry of Agriculture regulations for animal experimentation (1987).
Parasites and evaluation of the disease
Three different lines of Plasmodium were used: the BdS clone of PbA (10) which was kindly given by Dr. B. de Souza (Windeyer Institute for Medical Science, London, U.K.), P. yoelii yoelii 265BY, and P. chabaudi chabaudi clone AJ. Infected RBCs stabilates used to initiate infections were free from other infectious agents and were prepared through in vivo passage in C57BL/6J mice and stored in liquid nitrogen (107 parasitized erythrocytes/ml in Alsever’s solution). Mice were considered to have CM if they displayed the following neurological symptoms: paralysis, deviation of the head, ataxia, convulsions, and coma. One of the two brain hemispheres from mice displaying neurological symptoms was removed and fixed in Carnoy solution for 24 h, stored in butanol, and included in paraffin. For two animals per group, 5-µm sections from the midbrain region were stained with hemalun and eosin. Similar histological samples were obtained from infected but CM-negative mice at the same time of the infection.
Purification of whole brain-sequestered leukocytes (BSL)
Sacrificed mice were perfused intracardially with PBS to remove both circulating and nonadherent RBCs and leukocytes from the brain. The brain was then removed and adherent leukocytes isolated using a previously described protocol (15) with minor modifications. Brains were removed and crushed in RPMI medium (Life Technologies, Paisley, U.K.). The tissue-extract was then centrifuged at 400 x g for 5 min. The pellet was resuspended with 10 ml of an HEPES buffer containing 100 mM NaCl, 2 mM KCl, 0.3 mM Na2HPO4 12H2O, 0.01 M HEPES (Sigma-Aldrich, St. Quentin l’Arbresles, France), supplemented with 100 IU/ml of penicillin/streptomycin (Life Technologies), 0.05% collagenase (Boehringer Mannheim, Meylan, France), and 2 U/ml DNase (Sigma-Aldrich). The mixture was stirred at room temperature for 30 min. The tissue-extract was passed through a sterile gauze and centrifuged at 80 x g for 30 s to remove debris. The supernatant was deposited on a 30% Percoll gradient (Amersham Pharmacia Biotech, Uppsala, Sweden) and centrifuged at 1,400 x g for 10 min. The pellet was collected and residual RBCs were removed by hypotonic shock using ACK lysis buffer. BSL were resuspended in FACS buffer (PBS containing 1% FCS and 0.01% NaN3) and counted.
Immunolabeling and flow cytometry analysis of BSL
BSL were identified by their size (forward light scatter) and
granulosity (side light scatter) as previously described
(15). Macrophages were identified as
F4/80+ (biotinylated rat IgG2b mAb anti-mouse
F4/80, clone C1:A3-1; Tebu, Le Perray-en-Yvelines, France). Neutrophils
were identified as F4/80- and
Gr-1+ (rat IgG2b mAb anti-mouse Gr-1
conjugated to FITC, clone RB6-8C5; BD PharMingen, San Diego, CA).
Lymphocytes were identified by their small size and using the following
Abs: hamster IgG mAb anti-mouse CD3 conjugated to PE (clone 17A2;
BD PharMingen), hamster IgG mAb anti-mouse TCR 
conjugated to
PE (clone GL3; BD PharMingen), hamster IgG mAb anti-mouse
TCR conjugated to Quantum Red (QR) (clone H57-597;
Sigma-Aldrich), rat IgG2a mAb anti-mouse CD8 conjugated to FITC
(clone 53-6.7; BD PharMingen), rat IgG2a mAb anti-mouse CD8
conjugated to QR (clone 53-6.7; Sigma-Aldrich), rat IgG2a mAb
anti-mouse CD4 conjugated to QR (clone H129-19; Sigma-Aldrich), and
rat IgG2a mAb anti-mouse CD4 conjugated to PE (clone H129-19; BD
PharMingen), rat IgG2a mAb anti-mouse CD45R/B220 conjugated to
FITC, biotinylated hamster IgG mAb anti-mouse ICAM-1 (clone 3E2; BD
PharMingen), biotinylated rat IgG2a mAb anti-mouse LFA-1 (clone
2D7; BD PharMingen), biotinylated rat IgG2b mAb anti-mouse CD44
(clone IM7.8.1; Caltag Laboratories, Burlingame, CA), and biotinylated
hamster IgG mAb anti-mouse CD69 (clone H1-2F3; BD PharMingen),
mouse IgG2a mAb anti-mouse V8-1,2 conjugated to PE (clone MR5-2;
BD PharMingen), rat IgG2a mAb anti-mouse V2 (clone B20.6.5), and
rat IgG2a anti-mouse V6 (clone 44.22.1), (both a kind gift of G.
Chiocchia, Département d’Immunologie, Institut Cochin, Paris,
France) diluted at the appropriate concentration in FACS buffer.
Ultravidin-PE-conjugated (Leinco Technologies, St. Louis, MO) and goat
anti-rat IgG conjugated to FITC (Polysciences, Warrington, PA) were
used as secondary reagent. For each sample, 5,000 cells were analyzed.
The data were collected using a FACSCalibur flow cytometer analyzed
using the CellQuest software (BD Biosciences, Le Pont de Claix,
France). It has been previously shown that the collagenase treatment
used during leukocyte purification from the brain does not influence
the ability to detect cell surface markers including those analyzed in
this study (CD4, CD8, Gr-1, F4/80, CD44, LFA-1, CD62L, CD69, and
ICAM-1) (16, 17, 18, 19).
In vivo leukocyte subpopulation depletion
Rat IgG anti-mouse CD8 mAbs (clone 2.43; TIB 210; American Type Culture Collection (ATCC), Manassas, VA) were purified from ascites after ammonium sulfate precipitation. Anti-polymorphonuclear cells (PMNs) mAb (clone NIMP-R14) (20) and rat IgG anti-mouse CD4 (clone GK1.5; TIB 207; ATCC) mAbs were purified from supernatant after ammonium sulfate precipitation. A total of 1 mg of anti-CD8, anti-CD4, or anti-PMN mAbs was injected i.p. at day 6 after parasite injection close before the onset of CM. In one experiment, 1 mg of anti-CD8 mAb was injected when mice displayed neurological signs. In another experiment, 1 mg of anti-CD4 mAb was injected twice at day 0 and at day 4 postinfection with PbA. More than 98% of blood CD8+ or CD4+ T cells were depleted by this procedure as verified by FACS analysis using anti-CD4 (clone H129-19; Sigma-Aldrich) and anti-CD8 (clone 53-6.7; BD PharMingen) mAbs which recognized epitopes different from those recognized by the depleting mAbs. Depletion of blood neutrophils was >80% as verified by FACS analysis using anti-Gr-1 mAb. Purified rat IgG (Sigma-Aldrich) was used as a negative control.
Macrophages were depleted at day 5 after PbA injection by i.v.
injection of 0.2 ml of PBS containing 
1 mg of
dichloro-methylene-diphosphonate (Cl2-MDP)
encapsulated in liposomes (21). These liposomes were a
gift from Roche Diagnostics (Mannheim, Germany). More than 90% of
blood F4/80+ cells were depleted as verified by
FACS analysis 2 days later.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We relied on the ability of a cloned parasite line derived from
the PbA strain (10), henceforth referred to as PbA, to
induce CM in defined mouse strains. PbA-infected RBCs from this clone
cytoadhere in vivo to the cerebrum and the cerebellum vascular
endothelium (10). The C57BL/6J and 129/Ola mouse strains
generally all (90–100%) succumb of CM when infected with PbA.
However, when 129,B6 mice (derived from the two strains above) are
similarly infected, a reproducible proportion of mice (60–80%)
develop CM early in the infection (days 7–9) and die within <24 h
(Fig. 1
). In the remaining mice which do
not develop neurological signs (non-CM; NCM), the infection progresses
and the mice die of hyperparasitemia and anemia a week to 10 days later
(data not shown). CM in the mice is characterized by hemi- or
paraplegia, ataxia, convulsions, and coma. These symptoms are commonly
observed in the African child suffering from CM. We have exploited the
two pathologically distinct subgroups of 129,B6 mice in an internally
controlled analysis of the events which occur in the brain and which
lead to the neurological symptoms and the mortality associated with CM.
As a control, we used other host/parasite combinations: BALB/c mice
infected with PbA do not develop CM (Fig. 1A), but all die
of hyperparasitemia and anemia starting on day 9 postinfection (Fig. 1B and data not shown), while 129,B6 mice infected with
P. yoelii or P. chabaudi do not develop CM (Fig. 1A) and all mice survive and clear the infection (data not
shown).
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Histopathological observations of brain sections from mice with
and without neurological signs revealed the presence of infected RBCs
in both sample sets but characteristic petechial hemorrhages were
observed only in CM brains (data not shown). The other striking
difference concerned leukocytes in the microvessels, which were
relatively more numerous in CM brain sections as compared with NCM
ones. The distribution of the leukocytes in the capillaries was
observed to be uneven, reflecting observations in humans for both
leukocytes (22) and sequestered infected RBCs
(23). Therefore, we widened our investigations to include
the total number of adherent immune cells present in the whole brain.
Mice were sacrificed at different times during the infection, and
nonadherent circulating cells in the brain vasculature were removed by
extensive perfusion of the brain. The perfused brains were then
removed, crushed, and the cells dissociated. The adherent leukocytes
were then purified, and quantified and phenotyped by FACS analysis. The
total number of BSL obtained throughout infection was seen to increase
reproducibly in mice where the neurological signs of CM had appeared
(Fig. 2). FACS phenotyping, which was
subsequently performed for the isolated BSL, revealed an increase in
the numbers of macrophages, neutrophils, and T cells but not of that of
B cells (Table I).
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To establish whether any of the cell subsets where an increase was
observed were implicated in CM pathology, depletion experiments were
conducted close before manifestation of neurological signs. A role for
NK cells in CM had been excluded previously (8), and these
cells were not further investigated. The development of CM was not
abolished by either Ab depletion of neutrophils on day 6 postinfection
or by Cl2-MDP-mediated depletion of macrophages
on day 5 (Fig. 3). Thus, CM pathology
appears to be associated with brain-sequestered T lymphocytes. To
establish whether one or more of the T lymphocyte subsets were
implicated, we phenotyped these brain-sequestered cells from CM and NCM
mice (Table II). As compared with brains
of naive mice, the total and T cell numbers were twice as
high in the NCM brains but showed a 15- to 20-fold increase in CM
brains. Significant differences between CM and NCM whole brains in the
numbers observed for all the subsets of the whole brain-sequestered T
cells was taken as an indication for a putative causal role. The
numbers of and CD4+ T cells did not
significantly differ between the two infected groups (Table II), and Ab
depletion of CD4+ T cells at day 6 postinfection
did not prevent the development of CM (Fig. 4A). An effector role of
CD4+ T cells was thus excluded. Although the
number of CD8+ T cells tended to be higher
in the CM brains as compared with NCM brains, this difference was not
statistically significant (Table II). Exclusion of a pathogenic
effector role for all T cells is supported by experiments where
depletion of these cells at a time close to the onset of CM failed to
prevent the pathology (24). The two remaining putative CM
effector subsets were the CD8+ T cells
(4% of the BSL populations) and the
CD4-CD8- T cells. The
latter remarkably accounted for 90% of the sequestered T cells.
Because depletion of the double negative population is not feasible, we
tested whether Ab depletion of CD8+ T cells at
day 6 postinfection could prevent the development of CM (Fig. 4A). Depletion of CD8+ completely
abrogated the development of CM pathology with the mice dying of
hyperparasitemia and anemia in the third week postinfection (Fig. 4A), thus ascribing the effector role to
CD8+ T cells and excluding it for the double
negative. Analysis of the BSL populations from the
CD8+-depleted mice confirmed that the specific
depletion of these cells on day 6 did not significantly influence the
numbers or the phenotypic composition of the other brain-sequestered
cells, including the large numbers of
CD4-CD8- T cells (Fig. 4B). When CD8+ T cells were similarly
depleted in PbA-infected C57BL/6J and 129/Ola mice, the development and
mortality from CM were completely abrogated (0 of 10 mice in the
CD8-depleted groups vs 9 of 10 in the C57BL/6 control group and 10 of
10 mice in the 129/Ola control group). The essential role of
CD8+ T cells was confirmed by the use of
CD8+ T cell-deficient C57BL/6J mice (CD8 or TAP-1
knocked out (KO)). In these mice, infection by PbA did not lead to CM,
and all the mice died of hyperparasitemia and anemia in the third week
postinfection (Fig. 4C). We also analyzed the composition of
the BSL on day 7 postinfection in mouse-parasite combinations where CM
does not develop: P. yoelii and P. chabaudi
in the 129,B6 mice and PbA in BALB/c mice. The number of sequestered T
lymphocytes in the first two host-parasite combinations (P.
yoelii: 25,800 ± 11,600; P. chabaudi: 18,400
± 1,100) did not differ significantly from that observed in naive
129,B6 mice (36,200 ± 11,900). In BALB/c mice, a significant
increase (p < 0.05, Mann Whitney U
test) of leukocytes was observed in PbA-infected mice (526,000 ±
42,300) as compared with naive mice (298,600 ± 18,600). Although
a significant increase of the CD8+ T cells found
in the brain was observed in the infected mice, the actual numbers for
this subset were >20-fold lower than those found in PbA-infected
129,B6 CM mice (p < 0.005, Mann-Whitney
U test). It should be noted that the
CD4-CD8- T cells found in
the brains of these NCM BALB/c mice also represent >90% of the
brain-sequestered T lymphocytes, further confirming their lack of
involvement in CM pathology (Table III).
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Attempts to prevent the inevitable mortality of mice that developed patent neurological manifestations by the injection of anti-CD8 Abs were only partially successful. Mortality from CM was abrogated in 30% of the mice (3 of 10) injected with the depleting Ab, and all the mice (0 of 12) injected with the control Ab succumbed to CM.
Phenotyping of brain-sequestered CD8+ T cells
The activation status of the BSL CD8+ T cell
fraction from CM mice was analyzed (Fig. 5). The cells were enlarged indicating
that they had transformed into lymphoblasts and were activated. It was
interesting to note that >80% were CD69low,
CD44low, LFA-1low, or
ICAM-1low, an unusual phenotype for cells which
have migrated. Nonetheless, >90% of these cells were positive for two
chemokine receptors, CCR2 and CCR5, involved in trafficking (E.
Belnoue, F. T. M. Costa, A. M. Vigario, T. Voza, F. Gonnet, I. Landau,
N. Van Roorjen, M. Mack, W. A. Kuziel, and L. Rénia, manuscript
in preparation). It has been recently found that CD8
V8.1,2+ T cell numbers are increased in the
peripheral blood of CM mice, thus prompting the proposal that this cell
subset is specifically involved in CM pathogenesis (25).
Our results accord with this hypothesis as this subset formed 50% of
the CD8+ T cells (36% of total
CD8+ BSL) in BSL from CM mice (Fig. 6).
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Our results demonstrate an effector role for brain-sequestered
CD8+ T cells in mice at the time when CM
pathology is manifest. However, these observations do not preclude a
role for other peripheral leukocytes in the evolution of the CM
pathogenic process. A role for CD4+ T cells in
the induction of CM was brought to light when CM was abrogated in
CD4-deficient mice (Fig. 4
A). This was confirmed when Ab
depletion of these cells prevented the development of CM only when
conducted early in the infection but not immediately before the onset
of the neurological symptoms (Fig. 4A).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4% of the BSL). The low number of these pathogenic
cells was confirmed by histopathological staining, where only one to
two CD8+ T cells could be observed for sections
of 10–15 mm2 (data not shown). No evidence for a
specific localization could be noted despite careful examination of a
large number of brain sections. The role of these cells would have been
difficult to suspect from simple examination of a limited number of
human brain histopathological sections. Although the effector role of
CD8+ T cells is clear, other leukocyte
populations such as CD4+ T cells play a role in
the initiation of pathogenesis (6, 7, 8, 24, 25, 26, 27). Recent works by Chang et al. (28) have shown that CD8+ T cells mediate circulatory shock, vascular permeability changes, and edema in the brain and the lung during PbA infection. These results suggest that CD8+ T cells may induce pathological perturbations in other organs, possibly through an interactions with endothelial cells (ECs), thus reinforcing the role of these cells are a key effector in the severity of malaria.
Our findings suggest an immunological mechanism for the pathology of
CM. The pathological cascade is initiated when ECs are activated. This
is primarily due to parasite sequestration to the brain EC. Activation
of EC is known to be influenced by levels of circulating cytokines such
as TNF and IFN- (29), two cytokines in which production
is strongly induced by the malaria parasite (5, 30).
Activated EC can ingest parasite material (31) which could
be presented via MHC class I and II molecules often seen to be
up-regulated during the infection (32, 33). Effector
CD8+ T cells could then destroy those cells which
present parasite-derived Ags, thus leading to the breakdown of the
blood-brain barrier and the consequent pathology. Recent experiments
(34) indicate that perforin is necessary for CM mortality,
thus suggesting that the damage due to CD8+ T
cells is mediated by this pathway. Once initiated, the
CD8+ T cell-mediated damage might be difficult to
reverse, as indicated in our experiments. Clinically, the extent of the
damage and thus severity will depend on the level of EC activation and
the efficiency of CD8+ T cell recruitment. The
former is ultimately linked to parasitemia levels and the extent of
brain-specific sequestration of infected RBCs.
In conclusion, the data and the mechanism we present reinforce the
notion that the most important event to target in interventions aimed
at reducing the incidence of CM is the initiating event, i.e.,
sequestration of the parasites to the brain ECs. It is difficult to
envisage at present experimental scenarios where the pathogenic
potential of brain-sequestered CD8+ T cells can
be formally demonstrated in humans. It would be of great interest to
investigate whether a skewing of the TCR V repertoire of peripheral
CD8+ T cells, which has been elegantly
demonstrated in mice (25) and confirmed for the brain in
our experiments, also occurs in humans.
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Acknowledgments |
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Footnotes |
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2 Current address: Instituto Gulbenkian de Ciencias, Oieras, Lisbon, Portugal.
3 Address correspondence and reprint requests to Dr. Laurent Rénia, Département d’Immunologie, Institut Cochin, Hôpital Cochin, Bâtiment Gustave Roussy, 27 rue du Fbg St. Jacques, 75014 Paris, France. E-mail address: renia{at}cochin.inserm.fr
4 Abbreviations used in this paper: CM, cerebral malaria; NCM, non-CM; WT, wild type; KO, knocked out; BSL, whole brain-sequestered leukocyte; PbA, P. berghei ANKA; Cl2-MDP, dichloro-methylene-diphosphonate; EC, endothelial cell; PMN, polymorphonuclear cell; QR, Quantum Red.
Received for publication July 10, 2002. Accepted for publication September 30, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor-mediated but not tumor necrosis factor receptor type 1-or type 2-mediated signaling is crucial for the activation of cerebral blood vessel endothelial cells and microglia in murine Toxoplasma encephalitis. Am. J. Pathol. 154:1549. T-cell function in pathogenesis of cerebral malaria in mice infected with Plasmodium berghei ANKA. Infect. Immun. 67:446.8 during experimental cerebral malaria. Int. Immunol. 11:1553. and macrophages in Plasmodium berghei-induced cerebral malaria. Parasitology 107:125.
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 E. Belnoue, M. Kayibanda, J.-C. Deschemin, M. Viguier, M. Mack, W. A. Kuziel, and L. Renia CCR5 deficiency decreases susceptibility to experimental cerebral malaria Blood, June 1, 2003; 101(11): 4253 - 4259. [Abstract] [Full Text] [PDF]
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,
p = 0.0002 vs PbA-infected 129,B6 mice as
calculated by Fisher’s exact test. B, Survival curve of
129,B6 (circles, n = 11) and BALB/c mice infected
with PbA (
, n = 14). The data shown are
representative of four experiments. Mortality from CM (indicated by
•) occurs reproducibly in 60–80% of the infected 129,B6 mice.
Neurological signs first appear late on days 7–10 (shaded area), with
death occurring in <24 h of their onset. Parasitemia rarely exceeds
20% in these CM mice. In the NCM mice which survive beyond day 11, the
parasitemia rises up to 70% and they generally all succumb by day 25
as a result of hyperparasitemia and the associated anemia.
, Mice without any neurological
signs.
). *, p < 0.05, Mann-Whitney
U test vs nondepleted mice. C, Cumulative
incidence of CM in (left panel), and survival curve
(right panel) for PbA-infected C57BL/6 WT
(n = 11) and CD8+ T cell-deficient
mice: CD8 KO C57BL/6 (n = 6) and TAP-1 KO C57BL/6
(n = 6). 
