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CUTTING EDGE |







*
Laboratory of Pathophysiology, Regina Elena Cancer Institute, Rome, Italy;
Department of Immunobiology, DNAX Research Institute, Palo Alto, CA 94304;
Department of Experimental Medicine and Pathology, University of Rome, "La Sapienza", Rome, Italy;
§
Department of Genetics, University of Bari, Bari, Italy;
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Laboratory of Vascular Pathology, Istituto Dermopatico dellImmacolata, Rome, Italy; and
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Roche Institute, Milan, Italy
| Abstract |
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| Introduction |
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We have previously reported the molecular cloning of human CCR8, a T cell specific G-protein-coupled, 7-transmembrane receptor. This human receptor, previously known as TER1 (5), ChemR1 (6), or CKR-L1 (7), and now as CCR8, is functionally activated by the CC chemokine I-309 (8, 9) whose mouse homologue is T cell activation gene 3 (TCA-3)5. Human CCR8 is expressed only in lymphoid organs and in particular in the thymus (5, 7).
Th lymphocytes have been functionally separated into type 1 (Th1) and
type 2 (Th2) subsets based on their ability produce discrete sets of
cytokines (10). Th1 subsets produce IL-2, IFN-
, TNF-
, and
lymphotoxin and are believed to participate in cell-mediated immunity.
The Th2 subset produces IL-4, IL-5, IL-6, IL-10, and IL-13 and have
been associated with allergy-related phenomena and favor humoral
responses.
In this study we report the cloning of the murine CCR8 receptor (mCCR8). mCCR8 is also expressed mainly in the thymus. In the periphery, mCCR8 mRNA was found in significant amounts only in activated Th2 T cells. These cells respond in chemotaxis assays to known CCR8 ligands. These observations strongly suggest that mCCR8 is associated with Th2 responses and may represent a potential therapeutic target for intervention during allergic diseases.
| Materials and Methods |
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The open reading frame (ORF) of the human CCR8 gene was used as probe to screen the murine 129/SV genomic library in the l/fix vector (Stratagene, La Jolla, CA); phages were plated and hybridized with the labeled human CCR8 cDNA, and positive genomic phage clones were isolated, subcloned, and sequenced as previously described (5).
Analysis of mCCR8 mRNA expression by RT-PCR and Northern blot
RNA from purified cells were prepared with RNeasy total RNA kit (Qiagen, Chatsworth, CA), following the manufacturers instructions. mCCR8 expression was analyzed by RT-PCR using standard methods and 32P-labeled mCCR8 and hypoxanthine phosphoribosyltransferase (HPRT) probes.
Poly(A)+ RNA was extracted from cell lines using the FAST/TRACK method (Invitrogen, San Diego, CA) and from homogenized frozen tissues, from 4-wk-old BALB/c mice, using TRIZOL (Life Technologies, Gaithersburg, MD) followed by oligotex(dT) particles (Qiagen). Five micrograms of poly(A)+ RNA was subjected to Northern blot analysis as described (5).
Analysis of mCCR8 mRNA expression by Southern blot of cDNA libraries
For Southern blot analysis of cDNA libraries, 5 µg of excised cDNA was analyzed from each of various cells and tissue cDNA libraries constructed at DNAX. A probe corresponding to the coding region of mCCR8 was nonisotopically labeled using the DIG high-prime kit (Boehringer Mannheim, Indianapolis, IN) according to the manufacturers instructions, and hybridization was conducted under high stringency (0.2x SSC at 65°C). The blot was then developed using chemiluminescence.
Separation of mouse T cell subsets
Adult thymocyte subsets were separated as described (11).
Briefly, single cell suspensions of thymocytes were prepared from
6-wk-old BALB/c mice and stained with the following mAbs: anti-CD4
TriColor (Caltag, South San Francisco, CA), anti-CD8
(LyT2)
(53-6.7) phycoerythrin and anti-CD3
FITC (PharMingen, San Diego
CA). Single positive cells were gated and then sorted for expression of
CD3+CD4+ and CD3+CD8+
as well as double positive CD4+CD8+ cells. All
sorts yielded a purity of > 99% upon reanalysis.
Mouse polarized Th1/Th2 cells
Polarized Th1 and Th2 cells were derived from naive CD4+ T cells from DO-11.10 TCR transgenic mice with a TCR specific for the OVA peptide (OVA 323-339), as previously described (12). Their successful polarization was confirmed by analyzing their cytokine profile before use in other assays (data not shown). RNA was extracted from cell pellets using Qiagen RNeasy midi kits, following the manufacturers directions. Cell groups to be used for chemotaxis assays were stimulated in vitro for 5 h before use in the chemotaxis assays.
Human Th1 and Th2 lines
Human neonatal leukocytes were purified from freshly collected,
heparinized cord blood and Th cell lines generated as described (13).
Cells were washed and restimulated with 50 ng/ml PMA (Sigma, St. Louis,
MO) and 1 mg/ml ionomycin (Sigma) for 4 h. Brefeldin (10 mg/ml)
was added for the last 2 h of culture. Cells were then fixed with
4% paraformaldeyde, permeabilized with saponin, and stained with
FITC-labeled anti-IFN-
(PharMingen), phycoerthrin-labeled
anti-IL-4 (PharMingen), and Quantum red-labeled anti-CD4
(Sigma) Abs. Samples were analyzed by FACScan (Becton Dickinson).
Human Th1 and Th2 clones
The human Th1 and Th2 clones used here include the human Th1
clone ET 3.22 (specific for the hepatitis
antigen) and the Th2
clone E 4.1 (specific for Lo1 p1 allergen) that have been described
previously (14).
Chemotaxis assays
The chemotactic activity of highly polarized, mouse Th1/Th2 cells was assessed by microchemotaxis as described (1). The chemotactic index was calculated as the number of cells migrating in test well/number cells migrating in control well. Medium only (DMEM, no serum) was used as background control. Chemokinesis controls were included and were negative in all cases.
Ca2+ flux assay
Cells were washed and loaded with 2 mM Fluo-3AM for 30 min at 37°C (Molecular Probes, Eugene OR). Cells were washed and stained with quantum-red conjugated anti-CD4 Abs (Sigma). Cells were then analyzed in a FACStarPlus (Becton Dickinson). Flow cytometric analysis was gated only to the CD4+ cells monitoring emissions at 525 and 613 nm.
| Results and Discussion |
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Northern blot analysis using poly(A)+ RNA prepared from
several organs of a BALB/c mouse (Fig. 2
A) indicated that mCCR8 is
highly expressed in the thymus. Three mRNA species of about 4, 3, and 2
kb were identified for mCCR8, suggesting the existence of different
transcription initiation and/or polyadenylation sites. Goya et al. (17)
have recently reported similar observations.
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The distribution of mCCR8 among different thymic subpopulations was
monitored by RT-PCR followed by Southern blot analysis with mCCR8 or
HPRT (control) probes (Fig. 2
C) on single positive (SP)
CD4+CD8-CD3+,
CD4-CD8+CD3+, double positive (DP)
CD4+CD8+, or triple negative (TN)
CD4-CD8-CD3- thymocytes. mCCR8
message is abundant in CD4+ SP cells (lane
1) and detectable in DP cells (lane 3) but not
detectable in CD8+ SP (lane 2) or TN
cells (lane 4). This result indicates that CCR8 mRNA
expression is associated with the CD4+ lineage. The low
expression in DP thymocytes may represent cells committed to the
CD4+ lineage. This, along with the potential
anti-apoptotic effects discussed above, suggest that CCR8 signaling
may be involved in positive selection of thymocytes.
The distribution of mCCR8 mRNA in thymus sections was also analyzed by in situ hybridization. Expression was observed in both cortical and medullary thymocytes (data not shown). In the mouse spleen very few positive cells were observed in the T cell region of the white pulp (data not shown).
These results point to a T cell-specific expression pattern. Since only
the thymus expressed significant mCCR8 mRNA (Fig. 2
A), we
probed 28 mouse peripheral lymphoid tissues or hemopoietic cell line
cDNA libraries with mCCR8, including lymph nodes, spleen, T and B cell
populations, monocytes, and dendritic cells. Only a cDNA library from
activated, Th2-polarized cells expressed abundant mCCR8 (data not
shown). To confirm this, we analyzed various mouse T cell populations.
As shown in Figure 3
A,
activated Th2 cells strongly expressed mCCR8, and is also present in a
cDNA library from activated NK1.1+CD4+ T cells,
which are known to express several Th2-specific genes (19) and may
participate in Th2 differentiation through their ability to produce
IL-4. In contrast, mCCR8 mRNA was rare in an activated, polarized Th1
cell cDNA library (Fig. 3
A).
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We then produced highly polarized activated human Th1 or Th2 cells and
performed Northern blot analysis for human CCR8. As shown in Figure 3
C, activated human Th2-polarized cells showed strong
expression of human CCR8 whereas activated human Th1-polarized cells
did not. CCR4 has been recently reported to be preferentially expressed
in Th2 cells (14). As shown in Figure 4
,
we also observed strong CCR8 and CCR4 mRNA expression in the human Th2
clone E 4.1, but not in a human Th1 clone. These results suggest that
both CCR4 and CCR8 are potential markers for the differentiation of
human Th2 cells.
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inhibits the proliferation of
both Th2 cells (20) and CD4 thymocytes (21). This finding may represent
a mechanism through which Th1 cells can control the development of Th2
responses, and is due to the differential expression of IFN-
receptor in Th1 vs Th2 cells (22). Thus, CD4 thymocytes share some
characteristics with Th2 cells.
These data predict that Th2 cells should respond to CCR8 ligands. As
shown in Figure 5
A, I-309 and
TCA-3 are potent chemoattractants for activated Th2-polarized T cells.
Although activated Th1 T cells also respond to TCA-3, their response
required 1000-fold higher ligand concentration than Th2 cells. No
chemotaxis was observed by resting Th1, whereas only slight chemotaxis
(chemotactic index = 2.5) was observed with resting Th2 T cells
(not shown). Control experiments indicated that the responses observed
were due to chemotaxis, not chemokinesis (not shown). To our knowledge,
this is the first report of chemotactic activity of I-309/TCA-3 for T
cells, a result that reflects the high specificity of CCR8 expression
in activated Th2 T cells. Recently, CCR5 has been reported to be
preferentially expressed by Th1 cells (14, 23). In agreement with this
result, we observed that Th1-polarized mouse cells respond to
macrophage inflammatory protein-1
(MIP-1
) better than to TCA-3
(Fig. 5
B).
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Although the role of cytokines such as IL-4, IFN-
, and IL-12 in Th1
and Th2 development has been well documented (26), the role of
chemokines and their receptors in Th cell polarization and recruitment
remains poorly defined. The expression of chemokine receptors in Th1
and Th2 subsets may provide insights into the effects of these
molecules in Th responses. Both Th1 and Th2 cells can produce TCA-3
(27), indicating that they can affect Th2 migratory patterns. The
TCA-3/I-309-CCR8 interaction may also influence Th2 differentiation
and/or may have anti-apoptotic effects on these cells as well (18).
These observations have implications for therapy in allergic diseases
and point the way for future research.
| Acknowledgments |
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| Footnotes |
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2 This work was supported by funds from Ministry of Health and Italian Association Against Cancer (AIRC) to A.S. and from AIRC and Telethon to M.R. A.Z. is supported by a fellowship from AIRC. DNAX Research Institute is supported by the Schering-Plough Corporation. ![]()
3 These authors contributed equally to this work. ![]()
4 Address correspondence and reprint requests to Dr. Albert Zlotnik, DNAX Research Institute, 901 California Ave., Palo Alto, CA 94304. E-mail address: ![]()
5 Abbreviations used in this paper: TCA-3, T cell activation gene 3; m, murine; ORF, open reading frame; HPRT, hypoxanthine phosphoribosyltransferase; MIP-1
, macrophage inflammatory protein-1
. ![]()
Received for publication December 18, 1997. Accepted for publication May 19, 1998.
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