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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2533-2536
TECK, an Efficacious Chemoattractant for Human Thymocytes, Uses
GPR-9-6/CCR9 as a Specific Receptor
By
Byung-S. Youn,
Chang H. Kim,
Franklin O. Smith, and
Hal E. Broxmeyer
From the Departments of Microbiology/Immunology and Medicine, the
Walther Oncology Center, and the Herman B Wells Center for Pediatric
Research, Indiana University School of Medicine, Indianapolis, IN; and
the Walther Cancer Institute, Indianapolis, IN.
 |
ABSTRACT |
Chemokines regulate leukocytes trafficking in normal and
inflammation conditions. Thymus-seeding progenitors are made in bone marrow and migrate to the thymus where they undergo their maturation to
antigen-specific T cells. Immature T cells are in thymic cortex, while
mature thymocytes are in medulla. Chemokines may be important for
homing of thymus-seeding progenitors, and/or differential thymocyte
localization in thymus. Here we report that GPR-9-6, now called CC
chemokine receptor 9 (CCR9), is a receptor for thymus-expressed chemokine, TECK. Among a panel of chemokines tested, TECK specifically induced calcium flux in CCR9-expressing cell lines. We also showed that
TECK efficaciously induced chemotaxis of immature
CD4+CD8+ double-positive, and mature
CD4+ and CD8+ single-positive human
thymocytes. Our data suggest that TECK/CCR9 interaction may play a
pivotal role in T-cell migration in the thymus.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CHEMOKINES MEDIATE the migration and
activation of leukocytes. This primary function results from the
binding of chemokines to specific surface receptors, known as the
chemokine receptor superfamily.1-3 A growing body of
evidence clearly suggests that T cells differentially express a set of
chemokine receptors upon activation or differentiation such that
specific effector functions of T cells are made possible.4
Common lymphoid progenitor cells migrate from bone marrow to the fetal
thymus to initiate T-cell development. The T-cell maturation process
occurs in specific compartments in thymus.5 This
compartmentalizing process may be regulated by interactions between
chemokines and chemokine receptors. Several chemokines and/or their
cognate receptors have been implicated in T-cell migration in the
thymus.6,7 These include SDF-1, which binds the chemokine
receptor CXCR4; SLC and CK -11, which bind CCR7; and thymic-expressed
chemokine (TECK), whose receptor has not yet been identified. SDF-1
preferentially attracts immature murine
CD4 CD8 double-negative (DN) and
CD4+CD8+ double-positive (DP) subsets, while
SLC and CK-11 attract mature CD4+, and CD8+
single-positive (SP) subsets. Chemotactic specificity of TECK for human
or murine thymocyte subsets has not been reported.
Here we report that TECK7 is a specific ligand for an
orphan chemokine receptor-like protein known as GPR-9-6 and now
designated CCR9. Moreover, we show that TECK induces strong chemotaxis
of immature DP thymocytes, and CD4+ and CD8+ SP
human thymocytes, suggesting that the CCR9/TECK interaction plays an
important role in migration of T-cell progenitors in thymus.
| |
MATERIALS AND METHODS |
Chemokines.
Human TECK, MIP-1 , RANTES, MIP-1, Exodus-2, Eotaxin-2,
Fractalkine, MIP-4, LEC, MDC, TARC, Eotaxin, MCP-1 , I-TAC, ENA-78, and
MIG were purchased from Peprotech (Rocky Hill, NJ). Human ELC, GRO- ,
interleukin-8 (IL-8), SDF-1, and mouse TECK were purchased from R&D
systems (Minneapolis, MN). Lkn-1 was kindly provided by Dr Doo H. Park
(MOGAM Biotechnology Research Institute, Kyunggi-Do,
Korea). MPIF-1(CK8) was previously
described.8 BRAK was kindly provided by Dr Rob Hromas
(Indiana University School of Medicine).
Cell culture, fluorescence-activated cell-sorting analysis, and
transfection.
HEK 293 cells expressing EBNA were purchased from In Vitrogen
(Carlsbad, CA) and cultured in Dulbecco's modified Eagle medium (DMEM). Immunofluorescent staining was performed,
essentially as described in Pharmingen (San Diego, CA) technical
protocols. Cells were transfected using Fugene-6 (Roche, Indianapolis,
IN) with CCR1, CCR4, CCR5, CCR6, and GPR-9-6. Open reading frames encoding CCR1, CCR4, CCR5, and GPR-9-6 were directly amplified from
human genomic DNA with the use of polymerase chain reaction (PCR),
whereas CCR6 cDNA was kindly provided by Osamu Yoshie (Shionogi Institute for Medical Science, Osaka, Japan). After 48 hours, 200 µg/mL hygromycin B was added. Pools of hygromycin
B-resistant colonies were selected.
Construction of CCR9 expression vector.
The open reading frame previously known as GPR-9-6 (GenBank accession
no. U45982) was amplified with the following set of primers: forward
primer (5'-CCGGCTCGAGCCTATTCCTAACATGGCTGATGAC-3') and
reverse primer
(5'-CGCGGGATCCAAGACCCCTCAGAGGGAGAGTGC-3') using Pfu
polymerase (Stratagene, La Jolla, CA). The amplified fragment was
digested with XhoI/BamHI and cloned into pCEP4
(Invitrogen, Carlsbad, CA).
Northern blot.
The multiple-tissue Northern blots were purchased from Clontech (Palo
Alto, CA) and hybridized to GPR-9-6 or human -actin probe according
to the manual provided.
Calcium flux and chemotaxis assay.
Calcium flux was measured as previously described.8
Chemotaxis assays and preparation of thymocytes were performed as
previously described for mouse thymocytes.6 Human thymic
tissue was obtained with institutional review board
approval from 2-year-old cardiac surgery patients.
| |
RESULTS AND DISCUSSION |
To see whether thymus-specific chemokine receptors exist, we screened
expression patterns of known chemokine receptors and orphan receptors
using Northern blots as well as expression sequence tags (EST) through
GenBank. This screening led to identification of a cDNA previously
known as GPR-9-6 (GenBank accession no. U45982), whose expression was
highly restricted to thymus (Fig 1A). No other immune tissues expressed the 3.5-kb GPR-9-6 mRNA, suggesting that
GPR-9-6 could be a good candidate receptor involved in thymocyte migration. GPR-9-6 contains 7 putative transmembranes (TM) denoted by
overlines in Fig 1B. There is a potential N-glycosylation site (Asn20-Phe21-Thr22) in the
N-terminal segment. One notable feature is that the length of the
N-terminal segment is shortest among known chemokine receptors (Fig
1B). Considering the general role of the N-terminal segment of
chemokine receptors in ligand binding, the N-terminal segment of
GPR-9-6 may be involved in chemokine selectivity. The rank order of
amino acid identity of several known chemokine receptors to GPR-9-6 is
CCR7 (39%) > CCR6 (35%) = CCR5 (35%) > CCR1 (33%).
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| Fig 1.
Thymus-specific expression of GPR-9-6 and comparison of
the primary structure of GPR-9-6 with other chemokine receptors. (A)
Human immune system multiple-tissue Northern blot II and human
multiple-tissue Northern blot were sequentially hybridized to GPR-9-6
cDNA and human -actin probes at 68°C for 1 hour, washed with
0.1X standard saline citrate (SSC) at 50°C for 40 minutes, and exposed to x-ray films for 12 hours. (B) An alignment of
GPR-9-6 with CCR7, CCR6, CCR5, and CCR1 with the use of GeneWork 2.5.1. Putative transmembranes are indicated by overlines.
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To find a chemokine ligand for GPR-9-6, we searched the literature for
expression patterns of known chemokines. Among these chemokines, TECK
is produced by thymic dendritic cells,7 indicating that
TECK might be a ligand for GPR-9-6. We stimulated a panel of chemokine
receptor-expressing cell lines (CCR1, CCR4, CCR5, CCR6, GPR-9-6) with
human (h) TECK (hereafter termed TECK) and measured calcium flux. TECK
specifically induced a calcium flux in GPR-9-6 expressing cells in a
dose-dependent manner (Fig 2A and B).
Primary stimulation of GPR-9-6 expressing cells with TECK completely
desensitized the cells to TECK. We also tested 14 CC chemokines
(MIP-1, MIP-1, RANTES, Lkn-1, MCP-1, Eotaxin, Eotaxin-2, Exodus-2, ELC, MDC, TARC, MIP-4, LEC, and MPIF-1), 9 CXC chemokines (IL-8, Gro-, ENA78, I-TAC, GCP-2, MIG, IP10, SDF-1, and BRAK), and a CX3C chemokine (Fractalkine) in calcium flux assays.
These chemokines did not induce transient calcium mobilization in
GPR-9-6-expressing cells or influence the subsequent calcium flux
induced by TECK (data not shown), suggesting that TECK may be a
specific ligand for GPR-9-6. Mouse TECK (mTECK) also induced robust
calcium flux. Primary stimulation with mTECK partially desensitized the
cells to TECK. These data suggest that TECK is a specific ligand for GPR-9-6. There are currently 9 human CC chemokine receptors (CCR). Of
these receptors, CCR9, previously also known as D6 or CCR10, does not
appear to be a signaling receptor.9,10 Therefore, according
to the established nomenclature system, we propose GPR-9-6 to be
designated as human CCR9.
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| Fig 2.
Functional expression of GPR-9-6 and chemotactic behavior
of human thymocytes in response to TECK. (A) HEK293 cells were stably
transfected with CCR1, CCR4, CCR5, CCR6, and GPR-9-6. Transfected cells
were loaded with Fura-2AM and sequentially stimulated with the
chemokines (100 nmol/L) indicated. Transient calcium mobilization was
monitored by measuring relative fluorescence of Fura-2AM. (B)
Concentration dependence of calcium flux. Fura-2AM-loaded
GPR-9-6-expressing cells were stimulated with the indicated
concentrations of TECK (1 to 100 nmol/L), and fluorescence was
monitored. The peak amplitude of the calcium response was plotted. (C)
TECK is a broad-spectrum chemoattractant for immature and mature human
thymocyte subsets. (D) Comparison of chemotactic specificity of TECK
and SDF-1 for human thymocyte subsets. Input thymocytes before
chemotaxis and thymocytes migrated to control medium, TECK (3 µg/mL),
and SDF-1 (200 ng/mL) are shown with the percent composition of each
thymocyte subset shown in each panel. (E) TECK-induced chemotaxis of
human thymocytes is sensitive to pertussis toxin. Thymocytes were
pretreated with pertussis toxin (1 µg/mL) for 1 hour and used for
chemotaxis in response to TECK (3 µg/mL). Percent inhibition was
obtained from a formula [% Inhibition = 100  (% Cell Migration
With Pertussis Toxin Treatment Background Migration)/(% Cell
Migration Without Pertussis Toxin Treatment Background Migration)
×100].
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We examined recombinant TECK for its ability to attract T-cell subsets
in human thymus. TECK efficaciously attracted
CD4+CD8+ DP, CD4+, and
CD8+ SP thymocytes (Fig 2C). Chemotactic activity of TECK
for CD4CD8 (DN) thymocytes was
weaker than that for other subsets. TECK began to attract thymocytes at
concentrations around 1 µg/mL. At 3 µg/mL, a significant
percentage of each thymocyte subset (50% SP, 20% DP) was attracted to
TECK in 3 hours. Chemotactic specificity of TECK on human
thymocytes was similar to that of SDF-1 (Fig 2D), attracting all 4 immature and mature subsets of thymocytes. SDF-1 has been reported as a
chemoattractant for immature T-cell progenitors in mouse
thymus.6 Chemotaxis of human thymocytes to TECK was
completely abolished by pretreatment of thymocytes with pertussis toxin
(Fig 2E), suggesting that the TECK receptor, now called CCR9, signals
through pertussis toxin-sensitive Gi protein family proteins for chemotaxis.
TECK is expressed mainly in thymus and small intestine. In this regard,
TECK receptor appears to be specifically expressed in thymus,
suggesting a specific role of TECK in movement and production of T
cells. It is possible that this TECK receptor may be expressed in other
tissues, but below the detection limit of our present assessment. In
thymus, TECK is expressed from MHC II+ N418+
dendritic cells in thymic medullary stroma.11 Thymic
medulla is the place where SP thymocytes are localized and emigrate to the blood system.5 Thus, the expression pattern suggests
that TECK attracts DP thymocytes from thymic cortex to medulla. Our results that TECK efficaciously induces chemotaxis of DP thymocytes support this potential role of TECK in the thymus. Because TECK induces
chemotaxis of mature SP thymocytes as well, TECK appears to regulate
localization in medulla and emigration of SP thymocytes out of thymus.
In the mouse system, TECK has been shown to attract thymus seeding of
early fetal T-cell progenitors.11 However, because
pertussis toxin, but not neutralizing antibody to TECK, inhibits
seeding of thymus by progenitors, TECK may not be the only chemokine
that attracts these early T-cell progenitors. In this regard, SDF-1 may
be a potential chemokine that can perform this function, because it
induces chemotaxis of bone marrow CD34+ cells and very
early triple-negative thymocytes.
In summary, we have identified a thymus-specific chemokine receptor,
now called CCR9, which is a specific receptor for TECK. During the
review of this article, a publication by Zaballos et al12
reported that GPR-9-6 was a specific receptor for TECK and suggested
that the receptor be termed CCR9. TECK induces chemotaxis of immature
and mature thymocytes in a pertussis toxin-dependent manner,
suggesting that TECK/CCR9 interactions may be important for the
regulation of T-cell development. Obviously, elucidation of the
physiological roles of TECK/CCR9 system will be greatly facilitated by
generation of mutant mice lacking these respective genes.
| |
ACKNOWLEDGMENT |
We thank Dr John W. Brown (Indiana University) for help in obtaining
human thymic tissue.
| |
FOOTNOTES |
Submitted April 21, 1999; accepted June 4, 1999.
Supported by U.S. Public Health Service Grants No. R01 HL56416 and RO1
DK53674 from the National Institutes of Health to H.E.B.
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 Byung-S. Youn, PhD, Department of
Microbiology/Immunology and the Walther Oncology Center, Indiana
University School of Medicine, Bldg R4, Room 302, 1044 W Walnut St,
Indianapolis, IN 46202.
| |
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ABSTRACT
INTRODUCTION