International Immunology

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International Immunology, Vol. 11, No. 1, 81-88, January 1999
© 1999 Japanese Society for Immunology

Selective recruitment of CCR4-bearing T_h2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine

Toshio Imai, Morio Nagira, Shin Takagi, Mayumi Kakizaki, Miyuki Nishimura, Jianbin Wang¹, Patrick W. Gray², Kouji Matsushima¹ and Osamu Yoshie

Shionogi Institute for Medical Science, 2-5-1 Mishima, Settsu, Osaka 566-0022, Japan
¹ Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
² ICOS Corp., 22021 20th Avenue SE, Bothell WA 98021, USA

Correspondence to: T. Imai

	Abstract

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Helper T cells are classified into T_h1 and T_h2 subsets based on their profiles of cytokine production. T_h1 cells are involved in cell-mediated immunity, whereas T_h2 cells induce humoral responses. Selective recruitment of these two subsets depends on specific adhesion molecules and specific chemoattractants. Here, we demonstrate that the T cell-directed CC chemokine thymus and activation-regulated chemokine (TARC) was abundantly produced by monocytes treated with granulocyte macrophage colony stimulating factor (GM-CSF) or IL-3, especially in the presence of IL-4 and by dendritic cells derived from monocytes cultured with GM-CSF + IL-4. The receptor for TARC and another macrophage/dendritic cell-derived CC chemokine macrophage-derived chemokine (MDC) is CCR4, a G protein-coupled receptor. CCR4 was found to be expressed on ~20% of adult peripheral blood effector/memory CD4⁺ T cells. T cells attracted by TARC and MDC generated cell lines predominantly producing T_h2-type cytokines, IL-4 and IL-5. Fractionated CCR4⁺ cells but not CCR4^– cells also selectively gave rise to T_h2-type cell lines. When naive CD4⁺ T cells from adult peripheral blood were polarized in vitro, T_h2-type cells selectively expressed CCR4 and vigorously migrated toward TARC and MDC. Taken together, CCR4 is selectively expressed on T_h2-type T cells and antigen-presenting cells may recruit T_h2 cells expressing CCR4 by producing TARC and MDC in T_h2-dominant conditions.

Keywords: chemokine, chemokine receptor, chemotaxis, dendritic cells, T_h2 cells, transendothelial migration

	Introduction

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Close interactions between T cells and antigen-presenting cells (APC) are essential for initiation and promotion of antigen-specific immune responses. Immature dendritic cells uptake antigens while residing within tissues, migrate into lymphoid organs and differentiate into mature dendritic cells capable of activating naive T cells recirculating through the T-dependent areas of secondary lymphoid organs (1). Stimulated naive T cells then differentiate into memory/effector T cells that are classified into T_h1 and T_h2 subsets based on their profiles of cytokine production; T_h1 cells secrete cytokines such as lymphotoxin and IFN- to promote cellular immune responses, while T_h2 cells release cytokines such as IL-4 and IL-5 to promote humoral immunity and allergic responses (2). Differentiation into either of the two subsets is considered to be dependent on the nature of antigen, types of co-stimulatory molecules and cytokines present during the initiation of T cell response. Memory/effector T cells then migrate into the periphery and, upon activation by antigens presented on tissue APC, exert their effector functions by producing T_h1- or T_h2-type cytokines.

These two subsets are also recruited differentially depending on the type of inflammatory reactions to facilitate local immune responses (3). Since the balance between T_h1 and T_h2 responses determines the outcome of immune reactions and disease courses, the molecular settings mediating differential migration between the two T_h subsets are of great importance. Cell adhesion molecules and chemokines are known to play pivotal roles in the migratory properties of various leukocyte types and subsets (4–6). Recently, murine T_h1 cells but not T_h2 cells were shown to express the ligand for adhesion molecules P- and E-selectin, thus accounting for selective migration of T_h1 cells into inflamed tissues (3). Chemokines selective for T_h1 or T_h2 cells are also likely to be involved in the differential recruitment of these two subsets into inflamed tissues. In this context, differential expression of certain chemokine receptors in several T_h1 and T_h2 cell lines and clones have been reported (7–11). However, it has not been shown whether such differential expression of chemokine receptors exists in circulating memory/effector T cell subsets and accounts for their differential migration across vascular endothelium, a necessary step for tissue recruitment of each subset.

Here we demonstrate that a T cell-directed CC chemokine thymus and activation-regulated chemokine (TARC) (12) is produced by cytokine-stimulated monocytes especially under T_h2-dominant conditions as well as by monocyte-derived dendritic cells. CCR4 (13,14) is the receptor for TARC and another macrophage/dendritic cell-derived CC chemokine macrophage-derived chemokine (MDC) (15) and is expressed on ~20% of adult peripheral blood effector/memory T cells. TARC and MDC induced efficient transendothelial migration of fresh peripheral blood T cells, which gave rise to T cell lines predominantly producing T_h2-type cytokines. Fractionated CCR4⁺ T cells selectively generated T_h2 cell lines. T_h2 cell lines polarized in vitro from naive T cells expressed CCR4 at high levels and efficiently migrated toward TARC and MDC in transendothelial migration assays. Taken together, our results demonstrate that CCR4 is selectively expressed on the majority of T_h2 cells in adult peripheral blood and that APC such as monocytes/macrophages and dendritic cells produce TARC and MDC, especially in the presence of IL-4, to attract T_h2 cells. Thus, the T-cell-directed CC chemokines TARC and MDC and their receptor CCR4 may constitute important regulators of T_h2 responses.

	Methods

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Chemokines and mAb
Production and purification of TARC, MDC, eotaxin and secondary lymphoid-tissue chemokine (SLC) were described previously (12,15–17). RANTES was purchased from PeproTech (Rocky Hill, NJ). FITC–CD4 (Leu 3a), FITC–anti-CD14 (Leu M3), FITC–anti-CD19 (Leu 12), FITC–anti-CD8 (Leu 2a), FITC–CD45RA (Leu 18), R-phycoerythrin (PE)–CD45RO (UCHL1) and anti-CD45RO (UCHL1) were purchased from Becton Dickinson (San Jose, CA). PE–anti-CD3 (UCHT1), PE–CD4 (MT310), Cy5–CD4 (MT310), Cy5–CD8 (DK25) were purchased from Dako Japan (Kyoto, Japan). PE–CD16 (3G8) were purchased from PharMingen (San Diego, CA). Anti-CD16 (8G3), anti-CD14 (RMO52) and anti-CD20 (HRC20-B9E9) were purchased from Cosmobio (Tokyo, Japan). Anti-CD8 (OKT8) was obtained from the ATCC (Rockville, MA).

Determination of TARC production
Peripheral blood mononuclear cells (PBMC) were obtained from healthy adult donors using Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden). For isolation of CD14⁺ monocytes and CD14^– lymphocytes, PBMC were stained with FITC-conjugated anti-CD14 antibody and separated by MACS (Milteni Biotec, Bergisch, Germany). The purity of each cell population was 95–99% as determined by FACS. Dendritic cells were generated by culturing sorted CD14⁺ monocytes in RPMI 1640 with 10% FCS, 5 ng/ml granulocyte macrophage colony stimulating factor (GM-CSF; Genzyme, Cambridge, MA) and 10 ng/ml IL-4 (PeproTech) for 1 week as described (18). For production of TARC, cells were washed and incubated for 48 h without or with each stimulant: phytohemagglutinin (PHA, 1/100 dilution; Life Technologies, Grand Island, NY), 100 ng/ml lipopolysaccharide (0111:B4; Sigma, St Louis, MO), 10 ng/ml IL-1 (R & D Systems, Minneapolis, MN), 100 U/ml IL-2 (Shionogi, Osaka, Japan), 10 ng/ml IL-3 (Genzyme), 10 ng/ml IL-4, 50 ng/ml IL-7 (PeproTech), 50 ng/ml IL-10 (Genzyme), 5 ng/ml GM-CSF, 50 ng/ml TNF- (PeproTech), 1000 U/ml IFN- (Shionogi) and 10 ng/ml M-CSF (R & D Systems). The concentration of TARC in the supernatants was determined by a sandwich-type ELISA using Protein A-purified polyclonal anti-TARC antibody and biotinylated Protein A-purified polyclonal anti-TARC antibody. This ELISA dose not cross-react with other cytokines [IL-1, IL-2, IL-3, IL-4, IL-7, IL-10, TNF-, IFN-, macrophage colony stimulating factor (M-CSF) or GM-CSF] or chemokines (MCP-1, MCP-2, MCP-3, eotaxin, MIP-1, MIP-1ß, RANTES or IL-8) at 50 ng/ml.

Transendothelial migration assay
Transendothelial migration of leukocytes was assessed by using an endothelial cell line ECV304 as described (19,20). ECV304 (2x10⁵) were added to Transwell inserts (Costar, Cambridge, MA) with a 5 µm pore size and cultured at 37°C for 48–96 h in M199 with 10% FCS. Chemokines were diluted in a migration medium (RPMI 1640:M199 = 1:1, 0.5% BSA, 20 mM HEPES, pH 7.4) and added to 24-well tissue culture plates in a final volume of 600 µl. Endothelial cell-coated inserts were placed in each well and 10⁶ PBMC (Fig. 2A–C) or T cell lines (Fig. 4C) in 100 µl were added to the upper chambers. The cells were allowed to migrate through the endothelial cell layer into the lower chambers at 37°C for 4 h (PBMC) or 90 min (T cell lines). The migrated cells in the lower chambers were stained with FITC- or PE-conjugated mAb for indicated surface markers and counted by flow cytometry. In some experiments (Fig. 2D), CD4⁺CD45RO⁺ T cells were isolated from PBMC by negative selection with Dynabeads (Dynal, Lake Success, NY) after incubation with anti-CD16, anti-CD14, anti-CD20, anti-CD8 and anti-CD45RA antibodies, and used for transendothelial migration. Then, migrated cells in lower wells were expanded for 3–4 days with PHA (1:100) and 100 U/ml IL-2 in the presence of irradiated PBMC and for a further 8–10 days with 100 U/ml IL-2. Expanded cells were subjected to a second-round of enrichment by transendothelial migration. After re-expansion for further 12–14 days, cells were activated with 50 ng/ml phorbol myristate acetate (PMA; Sigma) and 1000 ng/ml ionomycin (Sigma) for 24 h. Cytokines in the supernatants were measured by ELISA (R & D Systems).

View larger version (32K): [in this window] [in a new window]   Fig. 2. Phenotypes and cytokine profiles of peripheral blood cells migrated toward TARC and MDC. (A) Transendothelial migration of PBMC to TARC and MDC. Lymphocytes migrated through a layer of the endothelial cell line ECV304. Representative data are shown (n = 7). (B) Phenotypes of lymphocytes migrating to 10 nM of TARC, MDC and RANTES. Representative data are shown (n = 4). (C) Selective migration of CD45RO+/CD45RA– effector/memory T cells by TARC and MDC. Surface expression of CD45RA and CD45RO in the gated CD4+ T cell population is shown (n = 3). (D) Production of IFN-, IL-4 and IL-5 by polyclonal T cell lines derived from CD4+/CD45RO+ T cells migrated to TARC and MDC. CD4+/CD45RO+ T cells were isolated from PBMC and used for transmigration. For comparison, total CD4+/CD45RO+ T cells were also examined. Representative data are shown (n = 3).

 

View larger version (47K): [in this window] [in a new window]   Fig. 4. Expression of CCR4 and migration toward TARC and MDC of Th2 cells differentiated from naive CD4+ T cells in vitro. (A) Surface CCR4 expression, and (B) CCR4, CCR3 and CCR7 mRNA expression in cell lines derived from peripheral CD4+/CD45RA+ naive T cells under Th1 (2 ng/ml IL-12 + 200 ng/ml anti-IL-4 mAb) and Th2 (10 ng/ml IL-4 + 2 µg/ml anti-IL-12 mAb) polarizing conditions. (C) Transendothelial migration of Th1 and Th2 cell lines in response to 10 nM of TARC, MDC and eotaxin or to 100 nM of SLC. Data shown are mean ± SEM from different donors (n = 3).

 
Isolation and characterization of CCR4^– and CCR4⁺ T cells
PBMC were incubated with an anti-CCR4 mAb (mouse IgG1) or a control mAb at 4°C for 30 min. After washing, cells were stained with FITC-conjugated anti-mouse IgG (Dako). After washing, cells were blocked with 1% normal mouse serum and then incubated with PE- or Cy5-labeled antibody for indicated cell surface markers. After washing, cells were analyzed on a FACStar Plus (Becton Dickinson). For isolation of CCR4⁺ and CCR4^– T cells, CD4⁺CD45RO⁺ T cells were obtained from PBMC by negative selection with Dynabeads (Dynal) after incubation with anti-CD16, anti-CD14, anti-CD20, anti-CD8 and anti-CD45RA antibodies, and further separated into CCR4^– and CCR4⁺ cells by sorting after staining with anti-CCR4 mAb. CCR4^– and CCR4⁺ T cells were expanded as polyclonal lines using PHA (diluted 1:100) and 100 U/ml IL-2 for 9–14 days. Expanded cells were subjected to a second round of enrichment by staining with anti-CCR4 mAb and sorting. Sorted cells were immediately activated with 50 ng/ml PMA and 1000 ng/ml ionomycin for 24 h and determined for cytokine production.

Generation and characterization of T_h1 and T_h2 cells
CD4⁺CD45RA⁺ naive T cells were obtained from human PBMC by negative selection with Dynabeads after incubation with anti-CD16, anti-CD14, anti-CD20, anti-CD8 and anti-CD45RO antibodies. Cells were activated with PHA (1:100) in the presence of 2 ng/ml IL-12 and 200 ng/ml anti-IL-4 mAb (MP4-25D2; PharMingen) for induction of T_h1 cells, or 10 ng/ml IL-4 and 2 µg/ml anti-IL-12 mAb (24910.1; R & D Systems) for induction of T_h2 cells. After 3–4 days, 100 U/ml IL-2 was added to the cultures. CCR4 expression and transmigration were analyzed at day 9–14.

Northern blot analysis
Total RNAs (5 µg each) were fractionated by electrophoresis on a 1% agarose gel containing 0.66 M formaldehyde. Gels were blotted onto a filter membrane (Hybond N⁺) (Amersham Japan, Tokyo, Japan). Hybridization was carried out at 65°C in QuickHyb solution (Stratagene, Palo Alto, CA) with probes labeled with ³²P using Prime it II (Stratagene). The probes for TARC, CCR4, CCR3 and CCR7 were described previously (12,14,16,21). After washing at 55°C with 0.2xSSC and 0.1% SDS, filters were exposed to X-ray films at –80°C with an intensifying screen.

	Results

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TARC production by monocytes and dendritic cells under T_h2-dominant conditions
Previously, we reported a novel T cell-specific CC chemokine TARC whose mRNA is constitutively expressed in the thymus and strongly induced in PHA-stimulated PBMC (12). In the present study, we developed an ELISA for TARC and examined the stimuli and types of cells that were involved in TARC production. As shown in Fig. 1(A), PBMC produced TARC when treated with GM-CSF, IL-3 or IL-4. GM-CSF was most potent in inducing TARC production followed by IL-3 (~2-fold less) and IL-4 (~5-fold less). In sharp contrast to most other CC and CXC chemokines, however, TARC was hardly induced by LPS or by pro-inflammatory cytokines such as IL-1, tumor necrosis factor- or IFN-. When PBMC were fractionated into lymphocytes and monocytes, monocytes produced TARC upon treatment with GM-CSF or IL-3 (Fig. 1B). On the other hand, none of the cytokines induced lymphocytes to produce TARC.

View larger version (24K): [in this window] [in a new window]   Fig. 1. TARC expression in monocytes and dendritic cells. TARC production was measured by an ELISA for TARC. (A) Induction of TARC production in PBMC by cytokines. Representative data are shown (n = 3) (B) Induction of TARC production in monocytes by GM-CSF, IL-3, and IL-4. Representative data are shown (n = 3). The amounts of TARC produced by stimulation with either GM-CSF or IL-3 alone (control) are 16.9 ± 8.4 and 9.9 ± 6.0 ng/106 cells/48 h respectively. (C) Effects of Th1 and Th2 cytokines on TARC production in PBMC. Data shown are mean ± SEM from different donors (n = 4). (D) TARC production in dendritic cells derived from CD14+ monocytes. TARC production is further increased by GM-CSF + IL-4. (E) Northern blot analysis of TARC mRNA.

 
GM-CSF and IL-3 are cytokines common to T_h1 and T_h2 cells, while IL-4 and IFN- are the key T_h2 and T_h1 cytokines respectively (2). We therefore examined the effects of IL-4 and IFN- on TARC production in PBMC stimulated by GM-CSF or IL-3. As shown in Fig. 1(C), TARC production was enhanced by IL-4 and suppressed by IFN-. IL-10, a potent inhibitor of cytokine production by T cells and monocytes (22), also suppressed TARC production. GM-CSF and IL-4 are also known to drive differentiation of monocytes into dendritic cells (18). As shown in Fig. 1(D), dendritic cells derived from monocytes cultured with GM-CSF + IL-4 produced large amounts of TARC. IL-4 also enhanced GM-CSF-induced TARC production ~2-fold by fully differentiated dendritic cells, but IFN- and IL-10 did not suppress TARC production (data not shown). Northern blot analysis further revealed that dendritic cells strongly expressed TARC mRNA, whereas fresh monocytes or macrophages derived from monocytes cultured with M-CSF did not (Fig. 1E). Thus, TARC is preferentially produced by monocytes in the milieu of T_h2 type cytokines and also by dendritic cells.

Selective migration of CD4⁺/CD45RO⁺/CD45RA^– effector/memory subset of T cells toward TARC and MDC
Previously, we demonstrated that CCR4 is the specific receptor for TARC and expressed selectively in CD4⁺ T cells (14). Recently we have further demonstrated that MDC, another CC chemokine produced by macrophages and dendritic cells (15), is a specific ligand for CCR4 (13). Therefore, we examined the phenotype of cells migrating toward TARC and MDC by using a transendothelial migration assay (20,23). As shown in Fig. 2(A), TARC and MDC induced vigorous migration of lymphocytes through a monolayer of an endothelial cell line ECV304. However, no migration was induced in monocytes (data not shown). MDC consistently attracted lymphocytes ~2 times more efficiently than TARC. Among lymphocytes, TARC and MDC attracted almost exclusively CD4⁺ T cells, while RANTES preferentially attracted CD8⁺ T cells (Fig. 2B). TARC and MDC were totally inactive on CD19⁺ B cells or CD16⁺ NK cells (Fig. 2B). Furthermore, TARC and MDC attracted almost exclusively CD45RA^–/CD45RO⁺ effector/memory cells (Fig. 2C). Effector/memory T_h cells represent the cells that have encountered cognate antigens in vivo and have differentiated into T_h1 or T_h2 cells. To analyze the T_h phenotypes of cells migrating toward TARC and MDC, CD4⁺CD45RO⁺ T cells were isolated and used for the transendothelial migration assay. T cells attracted by TARC or MDC as well as original CD4⁺CD45RO⁺ T cells were expanded with PHA + IL-2 and examined for the pattern of cytokine production. As shown in Fig. 2(D), the cells attracted by TARC or MDC were enriched for producers of IL-4 and IL-5, and depleted of producers of IFN-. This suggests that effector/memory T cells attracted by TARC and MDC were predominantly T_h2 cells.

Selective expression of CCR4 on T_h2 cells differentiated in vivo
To further define the phenotypes of T cells attracted by TARC and MDC, we used a mAb against the shared TARC/MDC receptor CCR4. This mAb specifically recognizes L1.2 cells transfected with CCR4 but not those with CCR1, CCR2B, CCR3, CCR5, CCR6, CCR7 or CX₃CR1 (to be published elsewhere). Consistent with the phenotype of lymphocytes migrating toward TARC and MDC, a mAb to CCR4 stained highly selectively a fraction (~20%) of CD45RO⁺CD4⁺ memory T_h cells (Fig. 3A). Since CCR4 is expressed on ~20% of effector/memory T_h cells, we next examined whether CCR4 is selectively expressed on certain subsets of T_h cells. By using the anti-CCR4 mAb, CD4⁺CD45RO⁺ T cells were fractionated into CCR4⁺ and CCR4^– subsets (Fig. 3B). After expansion with PHA + IL-2, CCR4⁺ and CCR4^– T cell subsets were examined for the pattern of cytokine production. As shown in Fig. 3(C), the CCR4⁺ subset but not the CCR4^– subset produced large amounts of IL-4 and IL-5. Conversely, the CCR4^– subset produced IFN- at levels much higher than the CCR4⁺ subset. Thus, CCR4⁺ T cells contained almost exclusively T_h2 cells, whereas CCR4^– T cells were enriched for T_h1 cells.

View larger version (49K): [in this window] [in a new window]   Fig. 3. Th2-type cytokine production by CCR4+ T cells. (A) Surface expression of CCR4 on a subset of CD4+/CD45RO+ lymphocytes. Freshly isolated peripheral blood lymphocytes were doubly stained for CD4 and CCR4 (left) or CD45RO and CCR4 (right). (B) CCR4 expression on cultured T cells after second sorting for CCR4– (left) and CCR4+ (right). (C) Production of IFN-, IL-4 and IL-5 by polyclonal T cell lines obtained from CCR4+ and CCR4– cells sorted from CD4+/CD45RO+ T cells. Cytokine production was measured by ELISA. Representative data are shown (n = 7).

 
T_h2 cells differentiated from naive CD4⁺/CD45RO^–/CD45RA⁺ T cells in vitro selectively express CCR4 and migrated toward TARC and MDC
To further strengthen the observed selective expression of CCR4 on T_h2 cells polarized in vivo, we polarized CD4⁺CD45RA⁺ naive T cells in vitro into T_h1 cells with IL-12 + anti-IL-4 or into T_h2 cells with IL-4 + anti-IL-12 (24). We confirmed that T_h1 cells selectively produced IFN-, and T_h2 cells produced a large amount of IL-4 and IL-5 (data not shown). As shown in Fig. 4(A), 60% of cells polarized into T_h2 cells expressed CCR4, whereas only 4% of T_h1 cells expressed CCR4. Northern blot analysis also demonstrated that T_h2 cells expressed CCR4 mRNA at levels much higher than T_h1 cells (Fig. 4B). As controls, CCR7 (21) was expressed in both types of cells, whereas CCR3 (16,19,25) was not detected in either type of cells. Consistent to the expression patterns of these CCR, the cells polarized into T_h2, but not those polarized into T_h1, migrated vigorously toward TARC and MDC (Fig. 4C), whereas both types of cells efficiently migrated toward SLC (17), a ligand for CCR7 (26). Neither T_h1- or T_h2-polarized cells migrated significantly toward eotaxin (16,23), a ligand for CCR3.

	Discussion

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In the present study, we have shown that the CC chemokine TARC is abundantly produced by monocytes stimulated with GM-CSF or IL-3 especially in the presence of IL-4 and by dendritic cells derived from monocytes cultured with GM-CSF + IL-4 (Fig. 1). Notably, TARC production is consistently promoted by the presence of IL-4, the key T_h2 cytokine. Furthermore, these particular cells are important APC whose interactions with migrating T cells constitute essential parts in initiation and promotion of immune responses (1). We speculate that enhanced production of TARC by APC in T_h2-dominant conditions facilitates selective recruitment of T_h2 cells expressing CCR4 (see below). Recruited T_h2 cells, upon activation by APC bearing cognate antigenic peptides, may produce cytokines such as IL-3, GM-CSF, IL-4 and IL-5, which further promote production of TARC from APC. Thus, TARC production by APC in T_h2-dominant conditions and selective expression of its receptor CCR4 by T_h2 cells may constitute a potential positive feedback system to facilitate T_h2-type responses.

Specifically, we have demonstrated that CCR4 is expressed on a substantial fraction (~20%) of adult peripheral blood CD4⁺/CD45RO⁺/CD45RA^– memory/effector T cells (Fig. 3). Consistently, TARC and MDC, another functional ligand for CCR4 produced by macrophage/dendritic cells (15), are capable of inducing efficient transendothelial migration of memory/effector T cells present in peripheral blood (Fig. 2). Furthermore, fresh CD4⁺ T cells attracted by TARC and MDC generated T cell lines preferentially producing IL-4 and IL-5 when compared with those derived from whole input memory/effector T_h cells (Fig. 2). This suggested that T_h2 cells selectively expressed CCR4, and were attracted by TARC and MDC. However, the presence of spontaneously migrating cells in chemotaxis assays brought about some ambiguity in the assignment of the T_h types attracted by TARC and MDC. We, therefore, fractionated fresh memory/effector CD4⁺ T cells into CCR4⁺ and CCR4^– subsets by using anti-CCR4 mAb and examined cytokine production after in vitro expansion. The results clearly demonstrated that CCR4⁺ cells selectively contained T_h2 cells, whereas CCR4^– cells selectively contained T_h1 cells (Fig. 3). While we do not exclude the possibility that T_h0 cells also express CCR4, selective expression of CCR4 on T_h0 cells instead of T_h2 cells is not likely. If CCR4 is selectively expressed on T_h0 cells, the CCR4^– subset would have generated cell lines containing both T_h1 and T_h2 cells that would produce IL-4 and IL-5 as well as IFN-. The CCR4^– fraction, however, showed dramatic depletion of cells capable of producing IL-4 and IL-5 (Fig. 3). We have further demonstrated that adult peripheral blood naive T cells polarized in vitro into T_h2 type but not those polarized into T_h1 type selectively express CCR4 at high levels, and efficiently migrated toward TARC and MDC (Fig. 4). From these results, we conclude that CCR4 is selectively expressed on peripheral blood T_h2 cells, although CCR4 expression on some T_h0 cells remains to be elucidated. Thus, CCR4 may provide a good surface marker for T_h2 cells and our monoclonal anti-CCR4 may be a useful reagent for evaluation of T_h1–T_h2 balance in peripheral blood T cells and tissue-infiltrating T cells.

Although we do not directly demonstrate the role of CCR4 in mediating chemotaxis by TARC and MDC (our monoclonal anti-CCR4 is non-neutralizing), several lines of evidence strongly support this prediction: (i) among 12 known chemokine receptors, eight CCR (CCR1–8), three CXCR (CXCR1, 2 and 4) and CX₃CR1, and four putative chemokine receptors examined so far, only CCR4-transfected cells migrated toward TARC and MDC, (ii) peripheral blood T cells attracted by TARC and MDC showed the same phenotypes, (iii) MDC was consistently ~2 times more efficient than TARC in chemotaxis assays for both peripheral blood T cells and CCR4-transfectants (13), and (iv) CCR4 expression on the cell surface correlated well with migratory responses toward TARC and MDC. Thus, CCR4 plays the major role in response to TARC and MDC, although we do not rule out the possibility that other receptors for TARC or MDC are expressed and regulated in parallel with CCR4.

Previously, Sallusto et al. (7) reported that the eotaxin receptor CCR3, which is mainly expressed on eosinophils and basophils (19,27), was expressed on a small fraction (~1%) of adult peripheral blood T cells, which selectively gave rise to T_h2 cell lines in vitro. Furthermore, T_h2 cell lines polarized in vitro from cord blood naive T cells comprised up to 50% of CCR3⁺ T cells (24). Bonecchi et al. (10) examined the expression of various chemokine receptors in T_h1 and T_h2 cell lines derived from cord blood naive T cells by in vitro polarization and found that T_h1 cell lines preferentially expressed CCR5 and CXCR3 mRNA, whereas T_h2 cell lines selectively expressed CCR4 and, to a lesser extent, CCR3 mRNA. Similarly, Loetscher et al. (9), by using T_h1 and T_h2 clones derived from cord blood, demonstrated that CCR5 was expressed at high levels in T_h1 clones and virtually absent from T_h2 clones, whereas CCR3 was undetectable in T_h1 clones and moderately expressed in T_h2 clones. They found that CXCR3 was expressed in both T_h1 and T_h2 clones although T_h1 clones expressed CXCR3 and responded to its ligand IP-10 at higher levels. Recently, Sallusto et al. (11) also showed specific expression of CCR4 mRNA and selective chemotaxis and calcium mobilization in response to TARC in T_h2 cell lines. Thus, the selective expression of CCR4 mRNA in several T_h2 cell lines is highly consistent with our present results demonstrating selective expression of CCR4 on the majority of T_h2 cells in adult peripheral blood T cells. We have not, however, detected any significant expression of CCR3 in our T_h2 cell lines polarized in vitro from adult peripheral blood CD4⁺CD45RA⁺ naive T cells. The discrepancy may be due to differences in experimental conditions or the source of naive T cells (adult peripheral blood versus cord blood). Furthermore, whereas the majority of eosinophils and basophils abundantly express CCR3 (19,27), only 1% of peripheral blood T cells were reported to express CCR3 (24). In spite of dramatic migration of eosinophils and basophils toward eotaxin (23,27,28), we and others have not observed any significant migration of peripheral blood T cells toward eotaxin, the ligand for CCR3 (23). Thus, the in vivo significance of CCR3 for recruitment of T_h2 cells from blood into tissues might be small, if any. Recently, Gerber et al. (8) reported that CCR3 was expressed only by a subset of T_h2 clones. Thus, CCR3 may play a role in activation and/or migration of some fully differentiated T_h2 cells. On the other hand, CCR4 is expressed on ~20% of peripheral blood effector/memory T_h cells and its ligands, TARC and MDC, induce efficient transendothelial migration of T_h2 cells. Thus, TARC and MDC, but not eotaxin, may represent the major attractants in selective recruitment of T_h2 cells through vascular endothelial cells into tissues.

Multiple chemokines are likely to be involved, sequentially and coordinately, in directed migration of T_h1 and T_h2 cells from blood into tissues and toward APC. Consistent to selective expression of CCR5, T_h1 cell lines and clones as well as peripheral blood T cells were shown to migrate toward its ligand MIP-1ß (9,10,29). However, CCR5 is expressed not only on T cells but also on monocytes, and its ligands, RANTES, MIP-1 and MIP-1ß, are produced by a wide variety of cells especially upon pro-inflammatory stimulation. Thus, the role of CCR5 in T_h1 recruitment may be closely associated with inflammatory responses. While CXCR3 may be selectively expressed in T_h1 cells (9,10), its ligand IP-10 was reported to be unable to induce transendothelial migration of T cells (29). Thus, CXCR3 may be involved in migration of T cells within tissues, not across vascular endothelium. We have shown that a recently identified lymphocyte-specific CC chemokine SLC induces efficient transendothelial migration of both T_h1 and T_h2 cell lines. Separately, we have reported that SLC broadly attracts T cells (CD4 and CD8 types as well as naive and memory subsets) and B cells (30). Recently, SLC has been shown to be expressed by high endothelial venules (HEV) and stromal elements in the T cells areas of secondary lymphoid organs, and to induce lymphocytes in flow conditions to rapidly adhere to intercellular adhesion molecule-1 through activation of ß₂ integrin (31,32). Thus, SLC may be a chemokine involved in emigration of a broad spectrum of circulating lymphocytes, including both naive T cells and memory T_h1 and T_h2 subsets, from blood into secondary lymphoid tissues via HEV. On the other hand, TARC and MDC are produced by APC preferentially in T_h2-dominant conditions and may recruit T_h2 cells expressing CCR4 from blood toward APC.

Although dendritic cells are distributed in various tissues, TARC and MDC are expressed strongly in the thymus but not in the spleen. In this context, dendritic cells were found to regulate T_h1 and T_h2 cytokine profiles in a fashion dependent upon their tissue of origin (33). TARC and MDC are also expressed in mucosal tissues where T_h2 cells are preferentially activated (12,15). Thus, production of TARC and MDC by APC and selective expression of CCR4 by T_h2 cells may represent an important biological amplification mechanism to promote local T_h2-type responses. Tissues of allergic inflammation are known to be infiltrated by T_h2 cells as well as eosinophils (34). T_h2 cells migrating into allergic tissues produce IL-4 and IL-5 upon antigenic challenge. These cytokines play key roles in the accumulation and activation of eosinophils and basophils (35,36). Suppression of T cell activation by glucocorticoids or cyclosporin A has been shown to reduce allergic inflammatory responses effectively (36). It remains to be determined whether TARC and MDC are major mediators that promote efficient tissue recruitment of T_h2 cells by APC in allergic diseases. In addition, TARC and MDC are constitutively expressed in the thymus (12,15) and may therefore play a role in the selective recruitment of CCR4-bearing thymocytes for their education and differentiation. Furthermore, MDC has recently been identified as an important suppresser factor for HIV-1 infection (37). HIV-1 was also shown to replicate preferentially in T cells producing T_h2-type cytokines (38). Thus, T_h2 cells, while potentially allowing higher viral replication than T_h1 cells, may be protected from viral infection by MDC, and most probably by TARC, via CCR4. Since CCR4 has little co-receptor activity (data not shown), MDC may suppress infection of HIV-1 by a mechanism that does not involve virus entry. Further characterization of signaling through CCR4 in T_h2 cells may provide a new strategy to prevent HIV infection.

	Acknowledgments

 
We thank Dr S. Harai in Kyowa Hakko Kogyo Co., Ltd, for providing an anti-CCR4 mAb. We also thank Drs Y. Himuna and M. Hatanaka for constant support.

	Abbreviations

 

APC	antigen-presenting cell
GM-CSF	granulocyte macrophage colony stimulating factor
HEV	high endothelial venules
MDC	macrophage-derived chemokine
PBMC	peripheral blood mononuclear cell
PE	phycoerythrin
PMA	phorbol myristate acetate
SLC	secondary lymphoid tissue chemokine
TARC	thymus and activation-regulated chemokine

	Notes

 
Transmitting editor: M. Miyasaka

Received 30 May 1998, accepted 1 October 1998.

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