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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4036-4039
The Viral Chemokine Macrophage Inflammatory Protein-II Is a
Selective Th2 Chemoattractant
By
S. Sozzani,
W. Luini,
G. Bianchi,
P. Allavena,
T.N.C. Wells,
M. Napolitano,
G. Bernardini,
A. Vecchi,
D. D'Ambrosio,
D. Mazzeo,
F. Sinigaglia,
A. Santoni,
E. Maggi,
S. Romagnani, and
A. Mantovani
From the Istituto di Ricerche Farmacologiche `Mario Negri,' Milan;
Section of Pathology and Immunology, Department Biotechnology,
University of Brescia, Brescia, Italy; Serono Pharmaceutical Research
Institute, Geneva, Switzerland; Istitute Dermopatico dell'Immacolata,
Rome; Regina Elena Cancer Institute, Rome; University of Rome "La
Sapienza," Rome; Roche Milano Ricerche, Milan; and Istituto di
Medicina Interna e Immunoallergologia, University of Florence,
Florence, Italy.
 |
ABSTRACT |
Kaposi's sarcoma (KS) lesions are characterized by a prominent
leukocyte infiltrate composed of mononuclear phagocytes and T cells.
KS-associated CD4+ and CD8+ cells showed
predominantly a type II cytokine profile. The CC chemokine viral
macrophage inflammatory protein-II (vMIP-II) encoded by the
KS-associated herpes virus 8 was a selective chemoattractant for T
helper 2 (Th2 cells) and for monocytes, whereas it was inactive on
other leukocytes, including Th1 cells, dendritic cells, and natural
killer (NK) cells. vMIP-II was an agonist for CCR8, a chemokine
receptor selectively expressed on CD4+ and
CD8+ cells with a type II cytokine profile. Hence,
vMIP-II has agonist activity for a chemokine receptor (CCR8), which is
preferentially expressed on polarized Th2 cells. The capacity of
vMIP-II to attract type II T cells selectively is likely to be a
component of the virus strategy to subvert the host immune response.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
HUMAN HERPES VIRUS 8 (HHV8), also known
as Kaposi's sarcoma virus, is associated with Kaposi's sarcoma (KS),
body cavity-based lymphoma, and Castelman's disease.1-4
The HHV8 genome includes three open reading frames coding for proteins
with considerable (~40%) identity to human CC chemokines and one
coding for a chemokine receptor, ORF74.5 KS is an
opportunistic tumor characterized by prominent angiogenesis and
leukocyte infiltration,6,7 including T cells and monocytes.
The current concept of the multistep process of leukocyte recruitment
into tissues envisions chemotactic agonists as one of the key effector
molecules.8-10 Chemokines are a superfamily of chemotactic
proteins that can be divided in four groups on the basis of a cysteine
structural motif. Most of the chemokines fall in two subfamilies: the
 (or CXC) chemokines, mainly active on neutrophils and lymphocytes
and the  (or CC) chemokines active on multiple subsets of
mononuclear cells. Lymphotactin ( or C chemokines) and fractalkine
( or CX3C chemokines) may define two additional groups of this
superfamily.10,11 Recent results indicate that polarized T
helper 1 (Th1) and Th2 populations differentially express chemokine
receptors and respond to chemotactic agonists.12,13
Here we show that CD4 and CD8 cells infiltrating KS have predominantly
a type II cytokine profile and that the KS chemokine viral macrophage
inflammatory protein-II (vMIP-II) is a selective attractant for type II
T cells and interacts as an agonist with a receptor (CCR8) selectively
expressed on this polarized subset.
| |
MATERIALS AND METHODS |
Preparation of effector cells.
Human monocytes and neutrophils were obtained from buffy coats of
healthy blood donors by density gradients on Ficoll (Biochrom) Percoll
(Pharmacia, Uppsala, Sweden), as previously described.14 Monocyte-derived dendritic cells (mono-DC) and CD34-derived dendritic cells (CD34-DC) were obtained as previously described.15
Stable transfectants of CCR8 (TER1) were prepared by electroporation of
Jurkat cells with pcDNA3-HA/TER1 and subsequent selection in G418.16 Th1 and Th2 cultures were obtained as previously
described.13
Migration assay.
Cell migration was evaluated using a chemotaxis microchamber technique
as previously described.14 Monocytes, neutrophils, DCs, and
Jurkat cells were tested using a 5-µm pore-size
polycarbonate filter. For Jurkat cells filters were previously coated
with murine collagen type IV. At the end of the incubation, filters
were removed, stained with Diff-Quik (Baxter s.p.a., Rome, Italy), and
five high-power oil-immersion fields were counted. T-cell cultures were
tested with the leading front methods using nitrocellulose filters, and
migration was evaluated as distance (µm) migrated by the two fastest
cells.14 Human recombinant MCP-3 (MCP-3) was a kind gift of
Dr A. Minty (Sanofi Elf Bio Recherches, Labège, France). vMIP-II
was chemically synthesized as previously described17 and
was a kind gift of Dr Ian Clark-Lewis (University of British Columbia,
Vancouver, Canada).
Generation of Th1, Th2, Tc1, and Tc2 lines from cord blood
leukocytes.
Generation of T helper cell lines was performed by stimulating cord
blood mononuclear cells with 2 µg/mL PHA (Wellcome, Beckenham, UK) in
polarizing conditions as described.18 Differentiation of
Th1 cells was obtained by addition of 2 ng/mL of IL-12 and 1,000 U/mL
of interferon- (IFN-; Hoffmann-La Roche Inc, Nutley, NJ) together with 200 ng/mL of neutralizing anti-interleukin-4 (IL-4)
antibodies (Pharmingen, San Diego, CA), whereas differentiation of Th2
cells was obtained by addition of 200 U/mL of IL-4 (Pharmingen) together with 2 µg/mL of neutralizing anti-IL-12 antibodies 17F7 and
20C2 (a gift of M. Gately, Hoffmann-La Roche Inc). Cells were evaluated
for their cytokine production profiles by intracellular staining as
previously described.13 Polarized CD4+ Th1 and
Th2 cells or CD8+ Tc1 and Tc2 cells were separated by
immunomagnetic negative selection by incubating the cells with anti-CD4
or anti-CD8 monoclonal antibodies (Pharmingen).
In vitro generation of T-lymphocyte clones from skin biopsies.
Skin biopsy specimens were incubated in IL-2 (20 U/mL)-containing
medium for 7 to 10 days to expand in vivo-activated IL-2 receptor-expressing T cells as previously described.19
T-cell suspensions obtained from each skin specimen were then cloned under limiting dilution conditions (0.5 cell/well) in the presence of
phytohemagglutinin (PHA; 1% vol/vol), IL-2 (20 U/mL), and irradiated peripheral blood mononuclear cells (PBMC) as feeder cells. The cell
surface phenotype of clonal T-cell blasts was assessed with flow
cytometry by using fluorescein isothiocyanate (FITC)-conjugated anti-CD3, anti-CD4, and anti-CD8 monoclonal antibodies (MoAbs). T
blasts (1 × 106/mL) from each clone were then
stimulated with PMA plus ionomycin for 24 hours, and the production of
IL-4 and IFN- was measured in cell-free culture supernatants by
using appropriate enzyme-linked immunosorbent assay (ELISA) assays.
| |
RESULTS AND DISCUSSION |
T-cell clones were generated under the same experimental conditions
from skin biopsy specimens of one normal volunteer, two patients with
alopecia areata, three patients with atopic dermatitis, and three
patients with KS. Higher proportions of CD8+ than
CD4+ T-cell clones were generated from the skin of KS
patients (369 and 53 clones, respectively), whereas CD4+
T-cell clones were prevalent in controls (53 and 14 clones for CD4+ and CD8+, respectively). As reported in
Fig 1, the majority of CD4+
T-cell clones generated from healthy skin or the skin of alopecia areata patients showed a Th1-skewed profile, whereas those generated from the skin of atopic dermatitis patients showed a more heterogeneous cytokine profile. However, virtually no CD8+ T-cell clones
with Tc2 profile, except in one patient with atopic dermatitis, were
found. By contrast, high proportions of both CD4+ and
CD8+ T-cell clones generated from the skin of KS patients
showed a Th2-skewed phenotype (Fig 1).
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| Fig 1.
Th2- and Tc2-skewed cytokine profile of
CD4+ and CD8+ T-cell clones generated from
the neoplastic skin of patients with KS. Clones were obtained from skin
biopsy specimens, taken for diagnostic purpose from three HIV-infected
patients with KS. As controls, cytokine production by T-cell clones
generated under the same experimental conditions from skin biopsy
specimens of one healthy volunteer, two patients with alopecia areata
(AA), and three patients with atopic dermatitis (AD) was evaluated.
Each symbol represents the amounts of IL-4 and IFN- produced by a
single CD4+ (open squares) or CD8+ (closed
circles) T-cell clone. Lines represent cutoff values (IFN-, 0.8 ng/mL; IL-4, 0.2 ng/mL), calculated as 5 SD over values found in
cultures containing feeder cells alone.
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The capacity of vMIP-II to elicit directional migration of various
leukocyte populations was then studied (Fig
2). vMIP-II induced migration of human monocytes with an ED50 of 32 ± 4 ng/mL (~3 nmol/L) and maximal activity at 100 ng/mL. Under
the same conditions MCP-3, used as reference chemoattractant, had an
ED50 of 15 ± 3, and the maximal response was 1.9 ± 0.3-fold (n = 3) higher than that of vMIP-II. Checkerboard analysis showed that vMIP-II elicited actual chemotactic migration in monocytes. This contrasts with previous data17 in which vMIP-II was a weak
monocyte attractant. This difference in vMIP-II efficacy is presumably due to the cell preparation and assay used. Other leukocyte
populations, neutrophils, monocyte-derived or CD34-derived dendritic
cells (Fig 2), NK cells, unseparated lymphocytes, and naive cord blood T cells (data not shown) showed no substantial response to vMIP-II.
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| Fig 2.
Agonist activity of vMIP-II. Monocytes (mono),
neutrophils (PMN), monocyte- and CD34-derived dendritic cells (mono-DC
and CD34-DC, respectively) and Jurkat (J) cells (A) or Th1 and Th2
cultures (B) were tested for their ability to migrate in response to
different concentrations of vMIP-II. (C) Northern blot analysis of CCR8
in Th1, Th2, Tc1 (Th1 CD8+), and Tc2 (Th2
CD8+) cultures.
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vMIP-II showed weak chemotactic activity for IL-2-activated, but not
resting, T cells (data not shown). These indications prompted a more
careful analysis of the capacity of vMIP-II to attract T-lymphocyte
subpopulations. As shown in Fig 2A, vMIP-II showed preferential
attraction of Th2 versus Th1 cells, both in bulk cultures and in clonal
populations. It has recently been shown that chemokine receptors are
differentially expressed in Th1 versus Th2
cells.12,13,16,20-22 CCR4 and CCR3 are expressed predominantly in Th2 cells, whereas Th1 cells express CCR5 and CXCR3.13 A similar differential expression of chemokine
receptors has been observed recently in CD8+ T cells with
different cytokine profiles23 (and unpublished results).
vMIP-II has been shown to interact with multiple chemokine receptors as
an antagonist or as an agonist.17,24 It binds
CCR3,24 a receptor expressed preferentially on polarized
Th2 cells,12,13,21,22 and shows activity on
eosinophils.24 As shown in Fig 2, vMIP-II interacts also
with CCR8, the I309 receptor,16,25,26 and elicits migration
of CCR8-transfected cells (J/CCR8; Fig 2A). Chemotactic index of J/CCR8
for vMIP-II was 5.3 ± 1.5 (n = 5) compared with 2.8 (n = 2) for
I-309 (at the peak concentrations of 100 ng/mL and 30 ng/mL,
respectively). Chemotactic index to SDF-1 (1 µg/mL), used as
reference chemoattractant, through its endogenous receptor (CXCR4), was
4.1 ± 0.3 (n = 4). As shown in Fig 2C, CCR8 was predominantly expressed in CD4+ Th2 cells and in CD8 T cells with a Th2
phenotype (Tc2). Hence, the ability of vMIP-II to act on chemokine
receptors, such as CCR8 that is expressed on Th2 cells, underlies the
ability of vMIP-II to selectively attract these cells.
Both CD4+ and CD8+ T cells comprise of
different subsets based on the cytokines they produce.27,28
Th1 cells predominantly mediate phagocyte-dependent protective immunity
as well as inflammatory autoimmune disorders, whereas Th2 cells are
responsible for phagocyte-independent protection and are prominent in
the pathogenesis of allergic diseases.28 The results
presented here show that KS lesions are infiltrated by CD8+
and CD4+ T cells with a predominant type II cytokine
profile. The viral chemokine encoded by KS-associated HHV8 was a
selective attractant for type II T cells and showed agonist activity
for CCR8, a receptor selectively expressed on polarized type II T
cells. There is evidence that activation of a Th2 response can lead to
delayed virus clearance.29 Hence, the capacity of the
HHV8-encoded chemokine vMIP-II to selectively attract monocytes and Th2
cells is likely a component of the virus strategy to subvert immunity.
| |
FOOTNOTES |
Submitted April 29, 1998;
accepted July 27, 1998.
Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) by
40% Fund (A.M.) and by special project AIDS from Istituto Superiore
Sanità, Grants No. 40A.0.66 (A.M.) and 30A.0.72 (A.V.).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to A. Mantovani, MD, Istituto di Ricerche
Farmacologiche `Mario Negri,' Via Eritrea 62, 20157 Milan, Italy;
e-mail: Mantovani{at}irfmn.mnegri.it.
| |
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Top
Abstract
Introduction