Table Of ContentTARC
Osamu Yoshie*
Department of Microbiology, Kinki University School of Medicine, 377-2 Ohno-Higashi,
Osaka, 589-8511, Japan
*corresponding author tel: +81-723-67-3606, fax: +81-723-67-3606, e-mail: [email protected]
DOI: 10.1006/rwcy.2000.11025.
SUMMARY N-terminal signal peptides (Imai et al., 1996). The
full-length cDNA was then isolated using the cDNA
fragment as a probe. TARC was found to be con-
Thymusandactivation-regulatedchemokine(TARC)
stitutivelyandselectivelyexpressedinthethymusand
is a CC chemokine constitutively expressed most
markedly, but rather slowly, induced in peripheral
prominently in the thymus and also to a lesser extent
bloodmononuclearcellsuponPHAstimulation(Imai
in tissues such as lung, colon, and small intestine.
et al., 1996). These features, which were noted to
TARC was the first CC chemokine shown to be
be quite unique among the hitherto known CC
chemotactic for lymphocytes but not for monocytes.
chemokines, led to its naming.
Itisproducedbydendriticcellsinvarioustissuesand
also by dendritic cells differentiated from blood
monocytes in vitro. TARC and MDC, another CC
Alternative names
chemokine that is very similar to TARC, act on
CCR4. In the thymus, CCR4 is expressed mainly on
CD4+ thymocytes in the cortex. Thus, TARC and TARC was described as such in 1996 (Imai et al.,
MDC,whichareexpressedinthemedullarydendritic 1996). Recently, murine TARC was reported by two
cells and epithelial cells respectively, may be involved groups (Lieberam and Foerster, 1999; Schaniel et al.,
in guiding the migration of positively selected CD4+ 1999). One group termed it ABCD-2 (Schaniel et al.,
thymocytes from cortex to medulla for negative 1999). Its systemic name proposed at the Keystone
selection. In peripheral blood, CCR4 is expressed Symposium in 1999 is CCL17 (Zlotnik and Yoshie,
by a subpopulation of CD4+CD45RO+ memory 2000).
T cells, which are mostly if not exclusively polarized
to TH2. Thus, it is likely that TARC and MDC
play important pathophysiological roles in TH2-type Structure
immune responses.
TARC is a typical CC chemokine with the four
conserved cysteine residues. The mature protein has
a molecular weight of 8083 and an isoelectric point
BACKGROUND
of 9.7. TARC is distantly related to other CC
chemokines. The amino acid identity of the mature
Discovery
TARC protein is 29% with RANTES, 28% with
MIP-1(cid:12) and MCP-3, 26% with MIP-1(cid:11), and 24%
TARC was cloned from freshly isolated normal with I-309, MCP-1, and MCP-2 (Imai et al., 1996).
peripheral blood mononuclear cells stimulated with TARC is most similar in amino acid sequence to
phytohemagglutinin(PHA) for72hours.The50 frag- MDC (Godiska et al., 1997), with 37% identity. It
ment of cDNA was originally identified by a method is notable that the genes for TARC, MDC, and
coined as signal sequence trap, which aims at the fractalkine are localized within 200kb on chromo-
selective isolation of cDNAs encoding secretory some 16q13 (Nomiyama et al., 1998). Furthermore,
and type I membrane proteins, i.e. those having TARC and MDC share CCR4 (Imai et al., 1997,
1298 Osamu Yoshie
1998). It is thus likely that TARC and MDC were chronically inflamed skin but not into the gastro-
generated by gene duplication from a common intestinal lamina propria was further demonstrated
ancestor. Human and murine TARC share a 65% (Campbell et al., 1999). TARC has been shown to
amino acid identity in their mature forms (Lieberam contribute to diverse disease states such as fulminant
and Foerster, 1999; Schaniel et al., 1999). hepatic failure, atopic dermatitis, Hodgkin’s disease,
and asthma.
Main activities and
pathophysiological roles GENE AND GENE REGULATION
Accession numbers
So far, the most relevant if not exclusive receptor for
TARCisCCR4(Imaietal.,1997).Thus,muchofthe
following discussion is also relevant for CCR4 GenBank
functions. Another CC chemokine, MDC, shares Human cDNA: D43767, NM_002987
CCR4with TARC(Imaiet al., 1998),butMDC may Mouse cDNA: AJ242587
alsoactonsomeotherunknownreceptor(s)(Bochner Human gene: AC004382
et al., 1999; Schaniel et al., 1999).
Chromosome location
Thymocyte Migration in the Thymus
One of the most notable features of TARC is its high
By somatic cell hybrid and radiation hybrid analyses,
constitutive expression in the thymus (Imai et al.,
the human TARC gene (SCYA17) has been mapped
1996). In the murine thymus, TARC is expressed by to chromosome 16q13 (Nomiyama et al., 1997).
medullary dendritic cells, while CCR4 is expressed Furthermore, the genes for TARC, MDC (SCYA22),
by CD4+ cortical thymocytes. Accordingly, it is and fractalkine (SCYD1) were found to be localized
postulatedthatTARCisinvolvedinthemigrationof
within 200kb of each other (Nomiyama et al., 1998).
positively selected CD4+thymocytes from the cortex
Themousegenesforthesethreechemokineswerealso
intothemedulla.MurineMDC,whichsharesmurine
found to be clustered within 130kb (Schaniel et al.,
CCR4with murine TARC,was alsoshown toattract
1999).
CD4+CD8low cortical thymocytes (Chantry et al.,
1999).
Cells and tissues that express
Selective Attraction of Memory T Cells the gene
In human peripheral blood, CCR4-expressing cells
were found to be a subset ((cid:24)20%) of CD4+ By northern blot analysis, TARC was shown to be
CD45RO+memory T cells. Accordingly, TARC as expressedmostprominentlyinthethymusandalsoin
well as MDC attracted CD4+CD45RO+ T cells tissues such as lung, colon, and small intestine (Imai
in vitro (Imai et al., 1999). Furthermore, T cells etal.,1996).Inthemurinethymus,TARCwasfound
expressing CCR4 were considered to be mostly to be expressed in the medullary dendritic cells.
polarized to TH2 since CCR4-positive T cells frac- In vitro, TARC was abundantly produced by human
tionated by anti-CCR4 and expanded with IL-2 pre- blood monocytes treated with GM-CSF or IL-3,
ferentially gave rise to T cells that, when stimulated, especially in the presence of IL-4, as well as by
produced IL-4 and IL-5 (Imai et al., 1999). In dendritic cells derived from monocytes treated with
agreementwiththis,TH2linesbutnotTH1lineswere GM-CSF+ IL-4 (Imai et al., 1999). TARC was also
foundpreferentiallytoexpressCCR4(Bonecchietal., found to be one of the highly expressed genes in
1998; Sallusto et al., 1998; Imai et al., 1999). In one dendritic cells derived from human blood monocytes
study, however, CCR4-expressing T cells were shown treatedwithGM-CSF+IL-4+TNF(cid:11),asdetermined
to contain essentially all skin-homing memory T cells by the method of serial analysis of gene expression
expressing the cutaneous lymphocyte antigen (CLA), (Hashimoto et al., 1999). Expression of TARC was
whichnaturallycontainbothTH1andTH2cells,and also detected in a fraction of dendritic cells derived
a subset of other systemic memory T cells but not from murine bone marrow cells treated with GM-
intestinal ((cid:11)4(cid:12)7+) memory T cells (Campbell et al., CSF (Lieberam and Foerster, 1999).
1999). The anti-TARC reactivity of venules and the Invivo,TARCexpressionwasdetectedindendritic
infiltration of many CCR4(+) lymphocytes into cells derived from bone marrow and thymus at high
TARC 1299
levels, and in dendritic cells from lymph nodes and RECEPTOR UTILIZATION
CD11c+cellsfromthelungatlowerlevels(Lieberam
andFoerster,1999).TheexpressionofTARCmRNA
TARC has been shown to be a highly specific
was also induced in murine splenic mature B cells at
functional ligand for CCR4 (Imai et al., 1997).
low levels by stimulation with anti-CD40+ IL-4 or
Subsequently, MDC was also found to be a specific
anti-CD4 alone, and at higher levels by stimulation
ligand for CCR4 (Imai et al., 1998). CCR4 was
with anti-IgM (Schaniel et al., 1999). TARC expres-
originallyreportedasasharedreceptorforRANTES,
sionwasalsoseeninthebasalepidermisintheatopic
MIP-1(cid:11), and MCP-1. This conclusion was led by an
dermatitis-like skin lesions of NC/Nga mice and in a assaymeasuringthestimulationoftheCa2+-activated
murine keratinocytic PAM212 cells that were treated
chloride channel in Xenopus laevis oocytes that were
with TNF(cid:11), IFN(cid:13), or IL-1(cid:12) (Vestergaard et al.,
injected with CCR4 cRNA (Power et al., 1995).
1999).
However, in the studies using CCR4-transfected
mammalian cells, TARC, but not any of these three
CC chemokines, was shown to induce significant
PROTEIN
responses in both chemotactic and intracellular cal-
cium mobilization assays (Imai et al., 1997). A claim
Accession numbers that TARC was also a functional ligand for CCR8,
the receptor for I-309 (Bernardini et al., 1998), has
SwissProt: been refuted in a recent work (Garlisi et al., 1999).
Human TARC: Q92583
IN VITRO ACTIVITIES
Sequence
In vitro findings
See Figure 1.
Consistent with its highly selective expression in the
thymus, 125I-labeled TARC binds to some human
Important homologies T cell lines but not to other types of cell line.
Furthermore, 125I-labeled TARC binds to fresh and
TARC is most homologous to MDC. They share a PHA/PMA-activated peripheral blood lymphocytes
37% amino acid identity in their mature forms. but not to monocytes or neutrophils. Consistently,
Human and mouse TARC share a 65% amino acid TARC has been the first CC chemokine shown to be
identity(LieberamandFoerster,1999;Schanieletal., chemotacticforlymphoidcellsbutnotformonocytes
1999). or neutrophils (Imai et al., 1996). TARC was ori-
ginally shown to be chemotactic for the human T cell
linesHUT102andHUT78(Imaietal.,1996).Inlater
CELLULAR SOURCES AND studies, TARC was shown to be selectively chemo-
tactic for CD4+CD45RO+ memory T cells, which
TISSUE EXPRESSION
arepolarizedmostlyifnotexclusivelytoTH2inboth
humans and mice (Imai et al., 1999; Lieberam and
Cellular sources that produce
Foerster, 1999; Schaniel et al., 1999).
Dendritic cells are the major source of TARC. In
PATHOPHYSIOLOGICAL ROLES
the thymus, TARC is expressed constitutively by
medullary dendritic cells. In vitro, TARC is produced IN NORMAL HUMANS AND
constitutively by dendritic cells differentiated from
DISEASE STATES AND
peripheral blood monocytes (Hashimoto et al., 1999;
DIAGNOSTIC UTILITY
Imai et al., 1999).
Role in experiments of nature and
Figure 1 Amino acid sequence for human TARC. The disease states
signal peptide is underlined.
Hodgkin’slymphomaischaracterizedbythecombina-
tion of Reed–Sternberg (RS) cells and a prominent
1300 Osamu Yoshie
infiltration of lymphocytes, plasma cells, eosinophils, IN THERAPY
and histiocytes. The small lymphocytes immediately
surrounding the RS cells are mostly CD4+ T cells. Effects of therapy: Cytokine,
TARC was found to be expressed at a high level by
antibody to cytokine inhibitors, etc.
RS cells of the classical nodular sclerosis and mixed
cellularity subtypes of Hodgkin’s lymphoma. Fur-
thermore, lymphocytes surrounding RS cells were In a murine model of fulminant hepatitis, anti-TARC
shown to be CCR4-positive and TH2-like (van den wasshowntosuppressTcellinfiltrationintotheliver
Berg et al., 1999). TARC production by RS cells andprotectmicefromfatalliverdamages(Yoneyama
may contribute to immune escape mechanisms in et al., 1998). In a murine model of asthma, anti-
Hodgkin’s disease. TARC was shown to suppress eosinophilic infil-
tration and hyperreactivity of the airway (Kawasaki
et al., unpublished).
Role of TARC in Fulminant Hepatic Failure
The intravenous injection of heat-killed Propioni-
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