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Introduction |
irus-specific cytolysis is considered a major defense
function of CD8+ T lymphocytes that eliminate productively infected cells and control the viral load during the
asymptomatic stages after HIV infection (1). HIV-1-specific CTLs have been studied extensively, and it has been
shown that they are present in high numbers in the blood
and and tissues (2). However, specific CTL activity declines with the development of AIDS (5, 6). CD8+ T cells
are an important source of chemokines that were shown to
inhibit HIV entry into CD4-bearing cells and to limit infection in vitro (7) and in vivo (8). On the other hand,
chemokines are potent attractants of T lymphocytes and
NK cells (9) and could, therefore, enhance antiviral effector
functions by stimulating cytotoxicity. This action would
differ from the well-established role of some chemokines as
competitors for HIV coreceptor usage (10).
Monitoring of specific cytolytic activity is a way to assess
the antiviral defense of HIV-1-infected individuals (11,
12). Activated, CD8+ HIV-1-specific CTLs are known to
produce interferons and chemokines (13), but other factors
or mechanisms may contribute to their overall HIV-1-suppressive activity (7, 14). We have now studied the effects of
chemokines on PBMCs and PBMC-derived, HIV-1-specific CTL lines generated from HIV-1-infected individuals
who were monitored for several years. We present data indicating that the HIV-1-specific lytic activity of patient-derived CTLs is enhanced by RANTES (regulated on activation, normal T cell expressed and secreted), which acts on the CTLs through the chemokine receptor CCR3.
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Materials and Methods |
HIV-1-infected Donors.
The donors of PBMCs used to establish
CTL lines and target cells were eight HLA-typed, HIV-1-infected
patients from the French cohort IMMUNOCO with CD4+ T
lymphocyte counts between 150 and 1,050/µl. They were recruited in 1991 and were followed for 5 yr on the basis of clinical
and functional tests.
Generation of HIV-1-specific CTL Lines.
CTL lines were prepared according to established methods (11, 12). PBMCs were
isolated from the venous blood of HIV-1-infected individuals by
centrifugation in Ficoll-Hypaque density gradients (Eurobio, Les
Ulis, France) and were activated overnight with 1 µg/ml PHA
(HA-16; Murex Diagnostic Ltd., Dartford, England). Polyspecific
CTL lines were generated by coculture with irradiated autologous
PHA blasts, and CTL lines specific for the Pol epitope of HIV-1LAI
(amino acid 476-484) by coculture with irradiated autologous
PHA blasts that were pre-incubated for 2 h at 37°C with 10 µM of
the synthetic peptide 476-484 (15). The appropriate irradiated
PHA blasts were added every tenth day, and the cocultures were
performed in the presence of recombinant human IL-2 (20 U/ml; Boehringer Mannheim, Germany) supplied every third day. The
CTLs were used for the cytotoxicity assays after 20 d of coculture.
Target Cells.
Three types of target cells were used: autologous
EBV-transformed lymphoblastoid B cell lines infected with vaccinia virus expressing the HIV-1LAI proteins Gag, Pol, or Env; autologous EBV-transformed lymphoblastoid B cell lines pulsed
with the synthetic peptide 476-484 corresponding to the Pol
epitope of HIV-1LAI; and the human plasmocytoid cell line Hmy
cotransfected with the HLA-A2 and the HIV-1LAI nef genes. The
EBV-transformed lymphoblastoid B cell lines were established for
each CTL donor. Infection with wild-type vaccinia virus or with
vaccinia virus expressing the HIV-1LAI proteins Gag, Pol, or Env
(Transgene, Strasbourg, France) was performed for 18 h at 37°C
at a multiplicity of 5 PFU/cell. Pulsing was performed with 10 µM of the synthetic peptide 476-484 for 2 h at 37°C using EBV-transformed cells already labeled with 51Cr (12). EBV-transformed cells infected with wild-type vaccinia virus or not pulsed
with the synthetic Pol peptide and Hmy cells transfected with the
HLA-A2 gene alone were used as the corresponding controls.
The Hmy cell lines transfected with the HLA-A2 or HLA-A2 and the HIV-1LAI nef genes (16, 17) were provided by Dr. W. Biddison (National Institutes of Health, Bethesda, MD).
HIV-1-specific CTL Activity.
The target cells were labeled for
2 h at 37°C with 100 µCi per 106 cells Na51Cr (Amersham, Les
Ulis, France), and washed twice with culture medium. The target
cells were distributed in round-bottomed 96-well microtiter plates
(4 × 103 cells per well), and the effector cells were added at E/T
ratios ranging between 120:1 and 3:1. The plates were centrifuged
at 300 rpm for 2 min and incubated for 4 h at 37°C. The supernatants were then collected and 51Cr-release was measured in a
gamma counter. The relative specific 51Cr-release was calculated as
previously described (12). Values for spontaneous 51Cr-release,
which are deducted in the calculation, were between 10 and 20%
of the total incorporated radioactivity. The results are presented
after subtraction of the nonspecific lysis obtained with control targets. All experiments were performed in triplicate. SE of triplicates
was always <5% of the mean value and was omitted for clarity.
NK and Lymphokine-activated Killer Cell Generation and Activity.
PBMCs from healthy donors were isolated by centrifugation in a
Ficoll-Hypaque density gradient and were immediately tested for
NK activity on K562 target cells. Alternatively, the PBMCs were
cultured for 48 h with 100 U/ml of recombinant IL-2 and tested for lymphokine-activated killer (LAK) activity on Daudi target cells. The experiments were performed at E/T ratios ranging between 70:1 and 7:1. The conditions for the Cr release assays were
the same as for the experiments with CTLs.
Flow Cytometry.
CCR3 expression was assessed on effector
and target cells using anti-CCR3 (see Reagents). For double fluorescence analysis of PBMCs, 5 × 105 cells were incubated for 30 min at 4°C with 10 µg of anti-CCR3, washed with PBS, fixed
with 1% paraformaldehyde in PBS, and analyzed on a FACScan®
flow cytometer (Becton Dickinson, San Jose, CA). 104 events per
sample were collected and analyzed using the Cellquest software
(Becton Dickinson).
Reagents.
RPMI 1640 medium (Gibco Life Technologies,
Cergy Pontoise, France) supplemented with 10% heat-inactivated
FCS, and standard concentrations of L-glutamine, sodium pyruvate, penicillin, and streptomycin was used as the medium in all
cultures and for dissolving additions. The chemokines and the
chemokine antagonist RANTES(9-68) were prepared by chemical synthesis (18). If not stated otherwise they were added to the
assays at the time of mixing effector and target cells. RANTES
determination in cell supernatants was performed by ELISA
(R&D Systems, Minneapolis, MN) and the data were analyzed using the Softmax program (Molecular Devices, Sunnyvale, CA). A standard concentration curve was assayed with each analysis. Four neutralizing monoclonal antibodies were used: anti-RANTES (R&D Systems, Minneapolis, MN); anti-CCR3 (7B11; LeukoSite,
Cambridge, MA); anti-CD4 (IOT4; Immunotech, Marseille,
France); and anti-CD8 (B9-11; Immunotech). An anti-VLA6
monoclonal of the same isotype (Immunotech) was used as irrelevant antibody control. The antibodies were added to the suspension containing the CTLs shortly before mixing with the targets
at the concentration of 1 µg/ml, which was found, in concentration-dependence assays, to be sufficient for neutralization. Pretreatment of CTLs with Bordetella pertussis toxin (Sigma-Aldrich,
St. Quentin Fallavier, France) was performed for 1.5 h at 37°C in
the standard medium, followed by washing.
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Results and Discussion |
RANTES Enhances CTL Activity.
The effect of RANTES
on HIV-1-specific cytotoxicity was examined using polyspecific MHC class I-restricted CTL lines established from
HIV-1-infected donors that recognize the HIV-1LAI Env,
Pol, Gag, or Nef gene products. As shown in Fig. 1 A, the
specific lysis of autologous B cell lines expressing Gag, was
markedly enhanced by RANTES and was suppressed by a
RANTES-neutralizing antibody. Similar effects were obtained when the lytic activity of patient-derived HIV-1-
specific CTLs was tested with two other targets, autologous
B cells pulsed with a HIV-1 Pol peptide (Fig. 1 B) and a
human plasmocytoid cell line, Hmy, cotransfected with the
HLA-A2 and the HIV-1LAI nef genes (Fig. 1 C). By contrast, neither RANTES nor the RANTES-neutralizing antibody influenced the lysis mediated by blood-derived NK
or LAK cells, as illustrated for NK cells in Fig. 1 D. As
shown in Fig. 1 E, the enhancing effect of RANTES and
the inhibition of CTL activity by either neutralizing
RANTES or blocking its receptor with the antagonist RANTES(9-68) were regularly observed with several CTL
lines specific for Gag, Pol, or Env derived from HIV-1-
infected individuals. Together these results indicate that
RANTES was required for the lytic activity of HIV-1-specific CTLs of the cohort patients. Comparison of CTLs
from different individuals (Fig. 1 E) shows that the effects
were similar for different HIV-1 epitopes presented by the
target cells, and were highly reproducible. The use of different types of target cells (Fig. 1, A-C) indicates that the procedure used to induce expression of HIV-1-specific epitopes had no influence on the outcome of the experiments.
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Fig. 1.
RANTES enhances HIV-1-specific CTL activity. (A)
Transformed autologous B cells infected with recombinant vaccinia virus
expressing Gag HIV-1 antigens were used as targets. Lysis by HIV-1-specific CTLs was determined in the presence of 25 nM RANTES (closed
squares), 1 µg/ml anti-RANTES (open circles), or without additions (closed
circles). No lysis was obtained in the presence or absence of 25 nM
RANTES (open squares and closed triangles, respectively) when transformed
autologous B cells infected with wild-type recombinant vaccinia virus
were used as targets. Similar effects were obtained in eight experiments
with CTLs from different HIV-1-infected donors. (B) Transformed autologous B cells preincubated with the synthetic peptide 476-484 corresponding to the Pol epitope of HIV-1LAI were used as targets. Lysis by
HIV-1-specific CTLs was determined in the presence of 25 nM
RANTES (closed squares), 25 nM RANTES(9-68) (open squares), 1 µg/ml
anti-RANTES (open circles), or without additions (closed circles). Data from
one experiment. (C) Human plasmocytoid cells Hmy cotransformed with
the HLA-A2 and the HIV-1LAI nef genes were used as targets. Lysis by
HIV-1-specific CTLs was determined in the presence of 25 nM
RANTES (closed squares), 25 nM RANTES(9-68) (open squares), 1 µg/ml
anti-RANTES (open circles), or without additions (closed circles). The data
are representative for two experiments. (D) RANTES does not affect the
lytic activity of NK cells. Lysis of K562 target cells by NK cells obtained
from venous blood of healthy donors was determined in the presence of
25 nM RANTES (closed squares), 1 µg/ml anti-RANTES (open circles), or
without additions (open squares). The data are representative for four experiments. (E) Effects of 25 nM RANTES, 1 µg/ml anti-RANTES and
25 nM RANTES(9 68) on the activity of HIV-1-specific CTLs from
eight different donors. Transformed autologous B cells infected with recombinant vaccinia virus expressing Gag (squares), Pol (circles), or Env (triangles) were used as targets. Data are shown for an E/T ratio of 40:1. The
straight lines connect the lytic activity values obtained in the absence ()
or presence (+) of the added reagent as indicated.
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The effects of RANTES and RANTES(9-68) were concentration dependent (Fig. 2 A). Specific lysis was nearly
doubled at 10 nM RANTES and approached a maximum
between 50 and 100 nM, whereas inhibition by RANTES
(9-68) was observed above 25 nM and was nearly complete
at 50 and 100 nM. On the other hand, no effect was obtained with increasing concentrations of macrophage inflammatory protein (MIP)-1
. The concentrations shown
are similar to those required for leukocyte activation by
chemokines and the inhibition of functional responses by
chemokine antagonists (19). Since chemokine antagonists have lower receptor affinity than the chemokines
themselves (20), it is not surprising that higher concentrations of RANTES(9-68) were required to achieve a biological effect. As shown in Fig. 2 B, pretreatment of the
CTLs with increasing concentrations of pertussis toxin progressively decreased the cytolytic activity observed in the
presence of RANTES, indicating that the chemokine effect is mediated by a G protein-coupled receptor (9). Pertussis toxin also abrogated CTL activity in the absence of
added RANTES (data not shown). To identify the cells responding to RANTES, effector and target cells were pretreated separately before testing cytotoxicity (Fig. 2 C).
Pretreatment of the effector cells with RANTES yielded
similar results as shown in Fig. 1 when the chemokine was
added at the time of mixing effectors and targets. By contrast, no changes were observed when the same pretreatment was applied to the target cells. MIP-1 and MIP-1
,
which are produced by CD8+ T cells together with
RANTES (22, 23), were ineffective, as shown in Fig. 2 C
for MIP-1, suggesting that MIP-1 and MIP-1 do not
share the relevant receptor with RANTES. These results indicate that RANTES acts on the CTLs and has no toxic
or other apparent effect on the target cells. Additional support for this conclusion comes from the observed inhibition of the effect of RANTES after pretreatment of the
CTLs with pertussis toxin (Fig. 2 B).
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Fig. 2.
(A) Concentration
dependence of the effect of
RANTES on HIV-1-specific
cytolysis. Transformed autologous B cells infected with recombinant vaccinia virus expressing Gag were used as
targets. Lysis by HIV-1-specific
CTLs was assessed at an E/T
ratio of 120:1 in the presence
of increasing concentrations of
RANTES (closed circles), the antagonist RANTES(9-68) (open
circles), or MIP-1 (closed triangles). The data are representative for two experiments. (B)
Effect of B. pertussis toxin. The
effector cells were pretreated with RANTES in the absence (closed circles) or the presence (open circles) of pertussis toxin, washed, and then mixed with target cells expressing HIV-1 Pol protein. The toxin concentration was 10, 100, 1,000, or 5,000 ng/ml (open circles, top to bottom). The data are representative for four experiments. (C) RANTES acts on the HIV-1-specific CTLs but not on the target cells. Lysis was assessed at a similar E/T ratio after pretreatment of the effector (white bars) or the target cells (hatched bars) with RANTES, MIP-1 (all 25 nM) or without additions. Pretreatment was performed
for 1 h at 37°C followed by washing, immediately before the Cr-release assay. The data are representative for two experiments.
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CTL Activity Mediated by CCR3.
RANTES binds to
several receptors. It attracts monocytes (19, 24) and T lymphocytes (25) via CCR1, and eosinophils and basophils via
CCR3 (26, 27) and acts on T lymphocytes via CCR5 (28).
CCR4 was also reported as a candidate receptor (29), but
was later shown to bind a novel CC chemokine called
TARC (30). To identify the receptor involved in HIV-1-
specific CTL activity, we tested the effect of several well-characterized chemokines. As shown in Fig. 3, RANTES
could be substituted by eotaxin, monocyte chemotactic
protein (MCP)-3 and MCP-4, but not by MIP-1, MCP-1, or stromal cell-derived factor (SDF)-1. This suggests that
the observed HIV-1-specific CTL activity depends on
CCR3 and rules out effects via CCR1, CCR2, CCR5,
and CXCR4. To definitively prove the involvement of
CCR3, we used a monoclonal antibody that selectively blocks the function of this receptor (26). Fig. 3 shows that target cell lysis was abrogated in the presence of the antibody confirming that HIV-1-specific cytotoxicity is mediated by
chemokines that act via CCR3. Anti-CCR3 also prevented
the lysis of autologous B cells pulsed with a HIV-1 Pol peptide
476-484 and of the Hmy plasmocytoid cells expressing HLA-A2 and HIV-1LAI Nef, but had no effect on the lysis by NK
cells (data not shown). We tested the expression of CCR3 in
several HIV-1-specific CTL lines established from HIV-1-
infected individuals. The receptor was detectable in all lines,
and the percentage of positive cells varied between 3 and 10 depending on the donor. In no instance CCR3 was detected on the target cells (data not shown). Although several
chemokines that bind to CCR3 enhanced CTL activity,
RANTES appears to be the biologically relevant stimulus,
since lysis was virtually abolished when this chemokine was
selectively neutralized with the anti-RANTES antibody. It
has been previously reported that CD8+ T cells produce
RANTES and other CC chemokines (31). We have determined the production of RANTES by two CTL lines for
the duration of the cytotoxicity assay at an E/T ratio of 120:1,
and found concentrations of 52 ± 5 and 138 ± 22 pg/ml ± SD in the culture medium under conditions that yielded 20 and 40% specific lysis, respectively. These concentrations are
considerably lower than those added in this study to enhance
lysis. The low level of RANTES detected in these assays may
be related to the weak lytic activity observed even at high E/T
ratios. On the other hand, RANTES is likely to bind to CCR3
as it is released by the producing cells, and the assay in the
supernatant may underestimate the effective concentrations.
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Fig. 3.
Lysis by HIV-1-specific CTLs is
mediated by CCR3. Transformed autologous B
cells infected with recombinant vaccinia virus
expressing Gag were used as target cells. Lysis
by HIV-1-specific CTL lines obtained from
two individuals (A and B) was determined at an
E/T ratio of 120:1 in the presence of different
chemokines (all 25 nM), 25 nM RANTES(9-68), 1 µg/ml anti-RANTES, 1 µg/ml anti-CCR3, 1 µg/ml anti-CCR3 plus 25 nM
RANTES, or without additions. Similar effects
were obtained in eight experiments with CTLs
from different HIV-1-infected donors.
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After having shown that RANTES is a major mediator
of lysis by CTL lines derived from HIV-1-infected patients, it was important to assess whether the activity of
freshly isolated PBMCs was also RANTES-dependent. As
shown in Fig. 4, HIV-1-specific lysis by PBMCs that were
freshly isolated from infected individuals was enhanced by
RANTES and virtually abolished by antibodies that neutralize RANTES or block CCR3. In addition, Fig. 4
shows that CTL lines established from the PBMCs of both
donors lysed autologous but not mismatched targets. The
lytic activity was abrogated by anti-CD8 antibodies, both
in the presence and absence of RANTES indicating that it
was mediated by CD8+ T lymphocytes. Anti-CD4 antibodies, by contrast, were without effect (data not shown).
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Fig. 4.
(Top) RANTES enhances the CTL
activity of freshly isolated PBMCs. The lytic activity of PBMCs obtained from two HIV-1-
infected individuals (A and B) was assayed at an
E/T ratio of 120:1 against transformed autologous
B cells infected with recombinant vaccinia virus
expressing Pol (A) and Gag (B) in the presence of
25 nM RANTES, 1 µg/ml anti-RANTES,
1 µg/ml anti-CCR3, 1 µg/ml anti-CCR3 plus
25 nM RANTES, or without additions. (Middle
and bottom) RANTES activity is mediated by
MHC-restricted CD8+ T cells. HIV-1-specific
lysis by CTL lines derived from the PBMCs of
the same patients (A and B) was determined
against autologous and mismatched transformed
B cells infected with recombinant vaccinia virus
expressing Pol (A) and Gag (B) in the presence
of 25 nM RANTES, 1 µg/ml anti-RANTES,
1 µg/ml anti-CD8, 1 µg/ml anti-CD8 plus 25 nM RANTES, or without additions.
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This study shows that RANTES mediates the HIV-1-
specific killing of target cells by MHC-restricted CD8+ T
lymphocytes through a mechanism that depends on the
chemokine receptor CCR3. It is of interest that RANTES
is produced by CD8+ T cells after antigen-specific stimulation (35) and that CCR3 is expressed in CD4+ and CD8+
T lymphocytes (36). MIP-1, MIP-1, RANTES, and
MCP-1 were reported to enhance the proliferation of human T cells in response to anti-CD3 and of T cell clones
challenged with the relevant antigen (37), suggesting a role
of CC chemokines in the activation of polyclonal and antigen-specific cytotoxicity (38). A costimulatory function of
RANTES cannot be ruled out although the selectivity observed in this study suggests a different mechanism. Our
observations reveal a new facet of the antiviral properties of
RANTES. The involvement of CCR3 suggests the possibility to enhance its expression by CD8+ effector T cells in
order to prevent the decline of CTL activity in AIDS and
to improve cellular defense in other immunodeficiencies. In addition, retroviral gene transduction approaches could
be used to regulate the endogenous expression of
RANTES or RANTES-inducing cytokines.
Address correspondence to Patrice Debré, Laboratoire d'Immunologie Cellulaire, Bâtiment CERVI,
Hôpital Pitié-Salpétrière, Boulevard de l'Hopital 83, 75013 Paris, France. Phone: 33-1-4217-7482; Fax:
33-1-4217-7490; E-mail: patrice.debre{at}psl.ap-hop-paris.fr
This study was supported by the Agence Nationale pour la Recherche sur le Sida (ANRS), the Swiss
National Science Foundation (Grant 31-39744.93), and the Protein Engineering Network of Centers of
Excellence (PENCE), Canada.
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