(Journal of Leukocyte Biology. 2000;68:400-404.)
© 2000
by Society for Leukocyte Biology
Macrophage-derived chemokine (MDC)
Alberto Mantovani*,
,
Patrick A. Gray
,
Jo Van Damme
and
Silvano Sozzani*
* Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy;
Department Biotechnology, Section of General Pathology, University of Brescia, Italy;
ICOS Corporation, Bothell, Washington; and
Rega Institute for Medical Research, University of Leuven, Belgium
Correspondence: Silvano Sozzani, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail: sozzani{at}irfmn.mnegri.it
 |
ABSTRACT
|
|---|
Macrophage-derived chemokine (MDC) is a CC chemokine
paradigmatic of emerging aspects of chemokine immunobiology. It is
constitutively expressed, yet microbial products and cytokines regulate
its expression with divergent effects of type II (IL-4 and IL-13) and
type I (interferon) cytokines. Processing of the mature protein by
dipeptidyl peptidase IV/CD26 provides a further level of regulation. It
acts on diverse cellular targets including dendritic cells (DC), NK
cells, and T cell subsets. Among these, MDC is a potent attractant for
CCR4 expressing polarized Th2 and Tc2 cells, and evidence is consistent
with a role of this chemokine as an amplification loop of polarized
type II responses. Emerging indications on the involvement of MDC in
diverse pathologies, ranging from allergic reactions to HIV infection
and neoplasia, are discussed.
|
INTRODUCTION
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Macrophage-derived chemokine is a CC chemokine originally
identified in mature macrophages and termed MDC [1
,
2
] or stimulated T cell chemotactic protein (STCP-1)
[3
]. In addition, MDC was isolated in activated mouse
pro B cells and termed ABCD-1 [4
]. MDC provides a
paradigm for several aspects of chemokine immunobiology that have
emerged recently, including the increasingly blurred distinction
between constitutive and inducible chemokines, the role of these
molecules in regulating the trafficking of polarized T cells, and the
existence of multiple levels of regulation including specific protein
processing [5
]. Here, we will concisely review current
understanding of the immunobiology of this chemokine and of its
emerging crucial role in immunopathology, ranging from allergic
reactions to neoplasia.
|
GENE AND PROTEIN STRUCTURE
|
|---|
The MDC gene is localized on chromosome 16 band q 13, where the
gene encoding thymus and activation-regulated chemokine (TARC) is also
localized. It is interesting that TARC has one of the closest sequence
similarities to MDC among chemokines (32%) and that both of these
molecules recognize CCR4. The gene consists of three exons and two
introns and shares great homology with RANTES (regulated on activation,
normal T expressed and secreted) in the size of exons and the location
of the intron-exon junction [4
]. The human MDC encoding
transcript is 3.4-kb long, relatively long by chemokine standards. It
contains three alu repeats in the 3' noncoding region
[1
]. The open reading frame is equivalent to a 93 amino
acid protein. The mature, secreted, unprocessed MDC protein consists of
69 amino acids.
|
RECEPTORS AND CELLULAR TARGETS
|
|---|
MDC recognizes CCR4, a receptor that is shared by TARC
[6
, 7
]. TARC has been suggested to bind
CCR8 also, unlike MDC [8
], although this finding has not
been reproduced in other cellular contexts [9
]. Although
CCR4 is the canonical cognate receptor for MDC, there is evidence that
this molecule may recognize other as yet unidentified receptors. Cells
such as natural killer (NK) cells have vanishingly low levels of CCR4
transcripts, yet they respond vigorously to MDC [1
].
Most importantly, as discussed below, processed MDC missing the first
two or four amino acids (MDC 3–69 and MDC 5–69) does not interact
with CCR4 and is unable to attract T cells, yet it still has
appreciable chemotactic activity for monocytes [10
,
11
]. The identity of MDC or truncated MDC receptors other
than CCR4 remains to be defined. The existence of putative MDC
receptors other than CCR4 cautions against equating CCR4 expression
with MDC responsiveness.
CCR4 is also recognized by the viral chemokine vMIPIII, which acts as
an agonist [12
], whereas other chemokines encoded by
HHV8, vMIPI, and vMIPII are agonists for CCR8 and CCR3
[13
].
In the original studies with MDC [1
, 3
],
this molecule was found to be active on chronically activated T cells,
activated NK cells, and monocytes, although the latter result was
originally controversial [1
, 3
]. In
addition, MDC was an extremely potent chemoattractant for immature
dendritic cells, more active (100-fold) on this cell type than on
monocytes [1
]. Subsequent analysis of the activity of
MDC on T cell subsets revealed that MDC is a selective chemoattractant
for polarized type II CD4+ and CD8+ T cells
[14
15
16
]. Following engagement of the T cell receptor
and CD28, CCR4 and CCR8 are transiently upregulated in polarized Th2 or
Tc2 cells, which become more responsive to appropriate ligands. The
same activation protocol upregulates CCR4 expression and MDC
responsiveness in polarized Th1 and Tc1 T cells also
[16
]. CCR4 is expressed in a subset of circulating
normal T cells. According to one study, circulating CCR4+ T
cells are polarized with a potential to express a type II cytokine
profile [17
]. On the other hand, more recent data
suggest that CCR4 is coexpressed with the skin-homing receptor CLA1 in
circulating T lymphocytes. These data suggest that CCR4 and TARC, which
unlike MDC expressed on endothelial cells, may be a skin homing
receptor agonist system [18
].
|
REGULATION
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|---|
Constitutive production
MDC was identified originally as a gene constitutively
expressed after differentiation of mononuclear phagocytes from
monocytes into macrophages [1
]. In the same study, it
was also found that monocyte-derived dendritic cells express very high
levels of MDC constitutively. In addition, constitutive expression of
MDC transcripts was detected in lymphoid organs, most prominently the
thymus, spleen, and lymph nodes, as well as the small intestine.
Analysis of cellular elements responsible for constitutive MDC
production in the thymus has revealed that epithelial cells express MDC
immunoreactivity strongly [19
]. In addition,
constitutive expression of MDC was found in lymphoid organ dendritic
cells [20
].
Regulated production
The original description that MDC is constitutively
expressed in lymphoid organs and immunocompetent cells
[1
] led to the view that this chemokine belonged to the
realm of the constitutively expressed chemokines [5
].
However, subsequent studies have shown that environmental signals
modulate production of MDC (Table 1
). It was first
found that lipopolysaccharide (LPS) and primary proinflammatory
cytokines [interleukin (IL)-1 and tumor necrosis factor (TNF)]
augment MDC expression in macrophages [3
, 4
,
21
]. Of paramount importance in relation to the general
significance of MDC was the observation that IL-4 (and IL-13) and
interferon (IFN)-
have divergent effects on MDC production in
mononuclear phagocytes [13
, 22
]. These
studies were prompted originally by the finding that MDC was a
preferential attractant for polarized type II T cells
[14
]. As predicted on the basis of this observation, it
was found that IL-4 and IL-13 stimulate MDC production, whereas IFN-
is a potent inhibitor [13
]. MDC production was observed
in Th1 and Th2 cells, and Th1 cell production was inhibited by IL-12
and IFN-
, two cytokines that promote the differentiation of Th1
cells [23
]. Interestingly, also in pro B cells, the
activation protocol that led to the identification of MDC included IL-4
[4
]. When T cells were examined, MDC production was
found to be preferentially associated with a type II cytokine profile
and inversely related to IFN- production [16
,
24
]. Moreover, IL-12 and IFN- suppressed MDC
production induced by T cell receptor triggering in Th1 cells
[23
]. Consistently with the in vitro
observation of preferential induction of MDC production by IL-4 and
IL-13, and with its selective activity for polarized type II T cells,
it was found that in mice and humans, MDC expression was preferentially
observed in type II reactions, including atopic dermatitis in NC/Nga
mice, mice with allergic airway disease, and humans with Mycosis
fungoides/Sezary syndrome or atopic dermatitis [24
25
26
27
].
These results, together with the preferential attraction of polarized
type II T cells, led to the postulate that MDC represents an important
amplification circuit of polarized type II responses
[5
].
Although MDC has been shown to be produced in a constitutive or
regulated way by hematopoietic elements and in vivo, by
epithelial cells in the thymus, we have been unable consistently to
detect MDC expression or production in endothelial cells obtained by
various sources and exposed to various cytokine cocktails (unpublished
results).
Protein processing
MDC is processed by the surface serin protease
dipeptidyl-peptidase IV/CD26 [10
, 11
]. CD26
removes the N terminal dipeptyde gly-pro, as expected on the basis of
the specificity of the classically defined enzyme specificity.
Subsequently, with a slower kinetics, MDC (3–69) is processed by
removal of the tyr-gly dipeptide with generation of MDC (5–69)
[11
]. CD26-processed MDC (5–69) lost the capacity to
interact with CCR4 and had little chemotactic activity on lymphocytes
and dendritic cells. However, MDC (5–69) was as active as MDC (1–69)
on monocytes [10
, 11
]. The
dipeptidyl-peptidase IV/CD26 is widely expressed and processes
chemokines other than MDC [28
, 29
].
However, CD26 has been shown to be expressed preferentially and
selectively on polarized type I T cells compared with polarized type II
Th2 cells [30
]. These results were confirmed recently in
a microarray analysis of transcripts differentially expressed in
polarized T cells (F. Sinigaglia, personal communication)
[31
]. Therefore CD26, expressed mainly on polarized type
I T cells, may represent a negative feedback loop for MDC-mediated
recruitment of polarized type II T cells (Fig. 1
).
|
ROLE IN PATHOPHYSIOLOGY
|
|---|
Normal traffic
The finding that MDC is constitutively expressed by diverse cell
types in vitro and in vivo has led to the
suggestion that constitutive expression of this molecule may be
important for regulating the trafficking and positioning of normal
cells. MDC is expressed at high levels in the thymus, and it is active
on medullary CD4 single positive thymocytes [19
,
32
]. The pattern of expression of MDC and its activity on
thymocyte subsets may suggest that this molecule is important for the
transit of thymocytes from the cortex to the medulla. Skin-homing
memory T cells, recognized on the basis of expression of CLA, express
CCR4, which may act as a homing-chemokine receptor for cutaneous
reaction [18
]. Because MDC is not expressed in a variety
of endothelial cells in vitro and in vivo
(unpublished results), it is unlikely that it plays a major role as an
agonist produced by endothelial cells encountered by circulating
lymphocytes. Endothelial cells have been shown to express TARC, a
potent agonist of CCR4 [18
]. MDC was described
originally as an extremely potent attractant for monocyte-derived
dendritic cells, more active on these antigen-presenting cells than on
monocytes [1
]. It may play a role in the normal
positioning of dendritic cells in tissues and lymphoid organs.
Type II responses
As already mentioned above, there is strong evidence that MDC is
involved in the generation and amplification of polarized type II
responses. It was originally observed that MDC is a preferential
attractant for polarized type II T cells [14
,
15
, 17
, 22
]. In addition,
polarizing type II cytokines (IL-4 and IL-13) are potent inducers of
MDC or amplifiers of its production, whereas IFN-, IFN-, and
IL-12 inhibit MDC production. Finally, type I T cells express
preferentially the dipeptidyl-peptidase IV/CD26, generating MDC (3–69)
and MDC (5–69), which do not attract type II T cells and do not
interact with CCR4. Therefore, these in vitro findings led
to the proposal that MDC is part of an amplification circuit of
polarized type II responses [5
, 13
,
14
]. Consistently with these in vitro
observations, high levels of MDC have been observed in situ
and in the circulation in polarized Th2 responses in mice and humans
[24
25
26
]. CD83+ skin dendritic cells present
in biopsis of allergic dermatitis (Th2 skewed disease) and contact
dermatitis (Th1 skewed disease), patients are strongly positive for MDC
production with a higher percentage of positive cells in atopic
dermatitis patients (unpublished results). In a recent careful
analysis, Lloyd et al. [26
] investigated the
relative importance of the MDC-CCR4 axis compared with the eotaxin-CCR3
axis. In a model of allergic airway inflammation, by investigating
in vivo expression and by using blocking antibodies, it was
concluded that the eotaxin pathway is only important in early stages of
the response, whereas the CCR4-MDC axis has a dominant role in effector
Th2 recruitment under condition of chronic, repeated antigen
stimulation.
Human immunodeficiency virus (HIV) infection
The role of MDC in the control of HIV infection has been
controversial. MDC was originally identified as a CD8 T cell protein
product capable of blocking HIV infection, by non-R5 using and R5 using
virus isolates [33
]. An immortalized T-cell clone was
used, and the molecule with anti-HIV activity lacked the first two
amino acids [33
]. This original finding has been
difficult to reproduce [34
]. Also, CD26-processed MDC
had a somewhat enhanced anti-HIV activity but still relatively modest
[10
]. The anti-HIV potential of MDC was recently
revisited [35
]. It was found that MDC inhibits the
replication of R5 HIV Bal in monocyte-derived macrophages but not in T
cells, although there was considerable donor-to-donor variability
[35
]. Interestingly, MDC did not affect the virus entry
or reverse transcription but acted at a later post-entry step. In the
same study, emphasis was put on the use of carefully controlled MDC
preparations to obtain reproducible antiviral activity
[35
], because at least some of the commercially
available preparations gave inconsistent results, associated with poor
quality of the protein.
Cancer
The role of MDC in neoplastic disorders has not been
investigated extensively. Recent evidence suggests that MDC may be
important in hematologic neoplasia (unpublished results)
[36
]. In particular, the MDC gene was identified
repeatedly during the high-throughput sequence of Hodgkin’s
disease-Reed Stenberg cDNA libraries [36
]. IL-13 has
been suggested to be an autocrine growth factor in Hodgkin’s disease.
In addition, a prominent eosinophil infiltrate is a hallmark of
Hodgkin’s disease lesions, which provide a paradigm for polarized type
II responses. The oncogenic virus HHV8 encodes three chemokines, which
attract polarized Th2 cells by interacting with CCR3, CCR4, and CCR8
[12
, 37
38
39
]. In vivo evidence
of diversion of effective antitumor responses has been obtained
[40
]. Whether MDC is used by other tumors to divert
effective antitumor responses remains to be
elucidated.
|
CONCLUDING REMARKS
|
|---|
The results summarized here briefly indicate that MDC is a
recently identified CC chemokine, which may play an important role in
homeostasis and pathophysiology. In many respects, MDC provides a
paradigm for the previously unsuspected complexities of individual
components of the chemokine system. MDC was classified originally as a
constitutively expressed chemokine [1
], but subsequent
work suggested that its production is highly regulated by inflammatory
signals also and that a further crucial level of regulation may be
represented by mature protein processing in a selective and polarized
way. The importance of this latter pathway of MDC regulation, as well
as of other similarly processed chemokines, is at present uncertain.
There is a strong need for analytical tools to identify processed
isoforms of MDC and similar chemokines to establish their actual
in vivo relevance. The effect of MDC on T cells is complex
and defies any simplistic interpretation [1
,
14
15
16
17
18
19
, 41
]. However, the available in
vivo evidence is strongly consistent with a view that the MDC-CCR4
axis is an important determinant of polarized type II responses.
Accordingly, MDC, as well as its canonical (CCR4) and noncanonical (see
above) receptors, may represent valuable targets for development of
novel therapeutic strategies.
|
ACKNOWLEDGEMENTS
|
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This work was supported by Istituto Superiore di
Sanità, Target Project on AIDS; Associazione Italiana per la
Ricerca sul Cancro; MURST Cofinanziamento 1998; and CNR (Target Project
Biotechnology and Biotechnology Program Legge 95/95).
|
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ABSTRACT
INTRODUCTION
