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* Research Center for Allergy and Immunology, RIKEN, Yokohama, Kanagawa, Japan;
Supramolecular Biology, International Graduate School of Arts and Sciences, Yokohama City University, Yokohama, Kanagawa, Japan;
Graduate School of Biostudies and Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan;
Institute of Gastroenterology, Tokyo Women’s Medical University; and
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Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The spatial distribution of immune cells in PPs is most likely controlled by chemokine-driven processes. For instance, CCL20 is constitutively expressed by the FAE in both mice and human (8, 9, 10). Similarly, murine CCL9 and its potential human counterpart, CCL23, are selectively produced by the FAE but not by intestinal epithelial cells (IECs) (6, 10 ). The receptors for these chemokines, CCR1 and CCR6, are expressed by myeloid DCs. The blockade of CCL9 with a neutralizing Ab results in the failure to recruit myeloid DCs into the subepithelial dome (SED) of PPs (6). CCR6-deficient mice also manifest altered localization of myeloid DCs in certain circumstances and the reduced size of PPs (11, 12, 13). Collectively, these data clearly indicate that FAE-derived chemokines contribute to the migration of myeloid cells, which may be important for the maintenance of microarchitecture in GALT. However, it remains unknown whether lymphocytes are also attracted to FAE-derived chemokines in the context of lympho-epithelial interaction.
We have recently performed transcriptome analysis of FAE and IECs using high-density oligonucleotide microarray (14) and found that the expression level of CXCL16 is remarkably higher in the FAE than in the IECs. CXCL16 is one of the two known chemokines that are associated with the plasma membrane through a mucin-like stalk and a transmembrane domain. The membrane-bound and soluble forms of CXCL16 have completely different physiological functions. Although the membrane-bound form functions as a cell adhesion molecule, a scavenger, and a phagocytic receptor for oxidized low-density lipoproteins and bacteria (15, 16), it functions as a soluble chemokine when proteolytically released (17, 18). To date, a disintegrin and metalloproteinase domain-10 (ADAM10) is thought to be the key regulator of CXCL16 shedding (19, 20). The expression of CXCL16 was first identified on Ag-primed DCs, and its receptor CXCR6/Bonzo, was detected on activated T cells, suggesting the role of CXCL16 as a mediator of DC-T cell interaction. Other studies have shown the expression of CXCL16 on bone marrow stromal cells, macrophages, and aortic smooth muscle cells in atherosclerotic lesions (16, 21, 22).
In this work we demonstrate that CXCL16 mRNA and protein are produced throughout the FAE. CXCR6 is moderately expressed by most CD8+ T cells and a subpopulation of CD4+ T cells in PPs, and its expression is highly up-regulated after in vitro activation. The activated T cells show migration and cell adhesion activities in response to CXCL16. Furthermore, the administration of CXCL16 neutralizing mAb significantly inhibited the migration of activated T cells to the SED. These results suggest that CXCL16 may function in promoting the interaction between the FAE and T cells, which could account for activated T cell trafficking and retention in the SED in GALT.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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BALB/c and C57BL/6J mice were purchased from CLEA Japan and maintained under specific pathogen-free conditions in RIKEN animal facilities until use in experiments at 7–10 wk old. In certain experiments, BALB/c mice were maintained under germfree (GF) or conventional (CV) conditions at the animal facility of the University of Tokyo as described (23). All animal experiments were approved by the Animal Research Committee of the RIKEN Yokohama Research Institute and of the University of Tokyo.
Isolation of the FAE and IECs
The FAE and IECs were isolated as described previously (14). Briefly, PPs were dissected from murine small intestine and soaked in HBSS containing 30 mM EDTA (pH 7.2). After incubation at room temperature for 20 min, the FAE was isolated by manipulation with a fine needle under a transillumination stereomicroscope (MZ12.5; Leica Microsystems). IECs were also isolated in the same manner from small pieces of the duodenum, the jejunum and the ileum after excluding PPs. The isolated epithelial sheets were almost exclusively composed of epithelial monolayers with trace amounts of lymphocytes (14).
Detection of chemokine mRNA expression
Total RNA was extracted from the FAE and IECs using a commercial kit (RNeasy; Qiagen). One microgram of total cellular RNA was reverse-transcribed using SuperScript II (Invitrogen). Chemokine mRNA expression of murine FAE and IECs was assessed with a mouse chemokines and receptors gene array (GE Array Q series; SuperArray) following the manufacturer’s instructions. Real-time PCR analysis was performed to quantify the CXCL16 mRNA expression level using the SYBR® Green PCR assay and an ABI Prism 7000 sequence detection system as described previously (24). The CXCL16 mRNA expression of each sample was calculated by extrapolating to a standard curve obtained with an authentic sample containing large amounts of CXCL16 mRNA, and the values calculated were normalized to the expression level of GAPDH. Amplification of the expected single products was confirmed using 1% agarose gels and ethidium bromide staining. The specific primers for murine chemokines are 5'-GGC TTT GGA CCC TTG TCT CTT G-3' (forward) and 5'-TTG CGC TCA AAG CAG TCC ACT-3' (reverse) for CXCL16 and 5'-TTCATACTGCCCTCTCCTTCCTC-3' (forward) and 5'-TGTAGGTCCGTGGTTGTGAGTTT-3' (reverse) for CCL9. Murine CCL20 and GAPDH primers were described elsewhere (24, 25).
In situ hybridization (ISH)
The full-length sequence of CXCL16 was amplified from FAE-derived cDNA by PCR using the primers 5'-GCGGATCCACCATGAGGCGGGGCTTTGGACC-3' (forward) and 5'-GGCTCGAGCTAGGGTCTTGGTTCAACAG-3' (reverse). The PCR product was digested by BamHI and XhoI and was ligated into pcDNA3.0 digested by the same enzymes. Digoxigenin-labeled RNA probe was prepared by in vitro transcription with T7 or SP6 RNA polymerase (Roche) using the above-mentioned plasmid vector digested by XhoI or BamHI as template, respectively. ISH was performed with a Discovery® automated ISH system and a RiboMap kit in accordance with the manufacturer’s instructions (Ventana Japan) as described previously (14). Briefly, 4% buffered formalin fixed sections of murine PPs were deparaffinized, treated with protease, and hybridized with 50 ng of murine CXCL16 (mCXCL16)-specific antisense riboprobe or the control sense probe for 6 h at 65°C. The sections were then incubated with biotin-labeled anti-digoxigenin Ab (Jackson ImmunoResearch Laboratories) for 20 min at 37°C, followed by incubation with alkaline phosphatase-conjugated streptavidin for 16 min at 37°C. The signal was detected with a BlueMap NBT/BCIP substrate kit (Ventana Japan), and the sections were counterstained with Nuclear Fast Red.
Immunohistochemistry
For CXCL16 immunostaining, 1% zinc sulfate/4% formalin (Richard-Allan Scientific)-fixed sections of murine PPs (5 µm) were deparaffinized, rehydrated, and treated with 0.3% H2O2 in PBS for 20 min at room temperature to block endogenous peroxidase activity. The sections were incubated with 0.5% blocking buffer (Roche) in PBS for 30 min at room temperature and then with 2 µg/ml goat anti-mouse CXCL16 polyclonal Ab (R&D Systems) or an identical concentration of control goat IgG overnight at 4°C. The binding of primary Ab was detected with 4 µg/ml biotinylated donkey anti-goat IgG (Jackson ImmunoResearch) followed by streptavidin-HRP (ABC Elite; Vector Laboratories), visualized with 3,3'-diaminobenzidine (DakoCytomation), and counterstained with hematoxylin (DakoCytomation. For immunofluorescence costaining, CXCL16-specific binding was visualized with tyramide-FITC (PerkinElmer) and counterstained with 10 µg/ml rhodamine-labeled Ulex europaeus agglutinin-1 (UEA-1) (Vector Laboratories) followed by DAPI. The specimens were analyzed with a DM-IRE2 confocal laser scanning microscope and Leica confocal software (Leica Microsystems).
For immunohistochemical analysis of human CXCL16, endoscopic biopsies were obtained from the noninflamed terminal ileum containing lymphoid follicles of human subjects. The biopsy samples were fixed in 1% zinc sulfate/4% formalin (Richard-Allan Scientific) and immunostained using goat anti-human CXCL16 polyclonal Ab (R&D Systems) as mentioned above for murine samples. The studies were approved by the Committee on Human Subjects in RIKEN and Tokyo Women’s Medical University.
The distribution of T cells in PPs was determined by immunofluorescence staining. Frozen sections (5 µm) of PPs were fixed with paraformaldehyde (BD Pharmingen) and incubated with anti-CD16/CD32 mAb (clone 93; eBioscience) for 30 min at room temperature to block nonspecific Fc binding, followed by 4 µg/ml biotinylated anti-CD3
mAb (145–2C11; BD Pharmingen) or control IgG and finally by Alexa 488-conjugated streptavidin (Invitrogen) and DAPI.
Preparation of PP lymphocytes
Murine PP lymphocytes were prepared according to a method described previously (14). Briefly, PPs were excised from the intestinal wall and dissociated with collagenase solution containing 0.5 mg/ml collagenase (Nitta gelatin), 0.5 mg/ml DNase I (Roche), 2% FBS, 100 U/ml penicillin, 100 µg/ml streptomycin, and 20 mM HEPES (pH 7.2) in RPMI 1640 (Invitrogen Life Technologies) at 37°C for 20 min to obtain single-cell suspensions. The cell dissociation was repeated again in fresh collagenase solution. The single-cell suspensions were pooled and washed with RPMI 1640 twice and subjected to Percoll gradient separation to remove epithelial cells. For the in vitro activation of T cells, PP lymphocytes were cultured in a plastic dish coated with anti-CD3 (145–2C11) and anti-CD28 (37.5) mAbs (BD Pharmingen) in RPMI 1640 medium supplemented with 10% FBS and 4 ng/ml IL-2 (R&D systems) for 3–4 days and further cultured for 2–3 days without stimulation.
Flow cytometric analysis
CXCR6-expressing cells were detected with mCXCL16-human Fc
fusion protein as described (18, 26). Briefly, PP lymphocytes were incubated with CXCL16-Fc fusion protein or control human Fc, and specific binding was detected with PE-conjugated anti-human Fc (Jackson ImmunoResearch). To characterize cell populations, PP lymphocytes were further stained with the following: FITC-conjugated mAbs against CD3 (145–2C11) and CD62L (MEL14); PE-conjugated mAbs against CD4 (GK1.5) and CD11c (HL3); PerCP-conjugated mAbs against CD8
(53-6.7) and B220 (RA3–6B2); and biotinylated mAbs against CD11b (M1/70), CD25 (7D4), and CD44 (IM7) in combination with streptavidin-PerCP and streptavidin-PE-Cy7 (all from BD Pharmingen). The stained cells were analyzed using FACSCalibur with CellQuest software (BD Biosciences).
Chemotaxis and cell adhesion assay
Chemotaxis assays using a 3-µm Transwell chamber (Corning Costar) were performed as described previously (27). Cell adhesion assay was performed essentially as described (26). Briefly, activated CD4+ or CD8+ T cells derived from PPs were suspended at 5 x 105/ml in RPMI 1640 medium containing 0.5% BSA and 20 mM HEPES (pH 7.4). The cell suspension was transferred to 24-well plates (0.2 ml/well), where CHO cells stably transfected with mCXCL16 or wild-type CHO cells were preseeded. After incubation for 60 min at 37°C, nonadherent cells were removed by extensive washing with PBS three times. Adherent T cells were recovered with cell dissociation buffer (Sigma) and counted by FACSCalibur (BD Bioscience).
In vivo neutralization of CXCL16
Activated PP T cells were labeled with a PKH26 red fluorescent cell linker kit (Sigma) following the manufacturer’s instructions. To neutralize the biological activity of CXCL16, female C57BL/6J mice received i.v. injections of 200 µg of anti-CXCL16 blocking mAb (clone 12–81) (26, 28) or control rat IgG at 16 h before and 4 h after transferring PKH26-labeled cells.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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To define FAE-specific chemokines, we first prepared total RNAs from the FAE and IECs (14) of the murine small intestine and compared their chemokine mRNA expression profiles. Among the 32 chemokines tested, 13 chemokine mRNAs were detected in either the FAE or IECs (Fig. 1). The expression profiles of the chemokines in the FAE were characterized by the increase in CCL9/MIP-, CCL20/MIP-3, and CXCL16 and by the decrease in CCL5/RANTES, CCL25/thymus-expressed chemokine, and CX3CL1/fractalkine, compared with those in the IECs. The FAE-specific expression of CXCL16 mRNA was further confirmed by quantitative real-time PCR and ISH analysis. In analogy with other FAE-specific chemokines such as CCL9 and CCL20 (6, 8, 9), the CXCL16 mRNA expression level was 5- or 15-fold higher in the FAE than in IECs from the small intestine or the colon, respectively (Fig. 2). ISH analysis of murine PPs showed that the transcripts of CXCL16 were distributed throughout the FAE (Fig. 3, A and B; arrowheads) but not in the villous epithelium (arrows).
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CXCL16 expression under GF condition
It is well known that the FAE contains a limited number of mucin-producing goblet cells that lead to reduced mucin protection in situ (4). The expression of brush border hydrolases in the FAE is also down-regulated as compared with that in IECs (29). This allows external Ags, including commensal bacteria, to easily access the FAE, which might be the reason why CXCL16 is up-regulated in the FAE. To confirm this hypothesis, we compared CXCL16 mRNA and protein expressions on the FAE of BALB/c mice maintained under GF and CV conditions. However, no differences in CXCL16 mRNA and protein expressions between those two conditions were observed (Fig. 6, A and B). This observation suggests that the expression of CXCL16 on the FAE is regulated autonomously rather than induced by the exposure to luminal bacteria.
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To identify the cells that respond to CXCL16, we analyzed PP cells for the expression of CXCR6/Bonzo, the receptor of CXCL16, using a fusion protein of mCXCL16 and the human IgG-Fc domain (18, 26). CXCR6/Bonzo was moderately expressed on most of the CD8+ T cells of PPs (Fig. 7A). The expression of CXCR6/Bonzo was also observed in a small subpopulation of CD4+ T cells. Because the CD4+ T cell population is approximately four times larger than the CD8+ T cell population in PPs, the total number of CXCR6+ cells was comparable between the CD4+ and CD8+ T cells (2.5 x 105 and 4 x 105 cells in PPs, respectively), despite the lower ratio of CXCR6+ expression on the CD4+ T cells. The CXCR6+ and CXCR6– CD4+ populations were further analyzed for CD44 and CD62L expression. The CXCR6– population was mainly composed of CD44lowCD62Lhigh cells (Fig. 7B). In contrast, the CXCR6+ population was predominantly CD44highCD62Llow, suggesting an activation-dependent expression of CXCR6 by the PP CD4+ T cells. Indeed, the CXCR6 expression on the CD4+ and CD8+ T cells was remarkably up-regulated by in vitro stimulation with anti-CD3/CD28 mAbs (Fig. 7A). This finding is consistent with previous studies that used murine splenic and human peripheral blood T cells (18, 30).
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To examine whether CXCR6 on PP T cells is functional, we first performed an in vitro chemotaxis assay. Both activated PP CD4+ and CD8+ T cells showed migration activity in response to the N-terminal chemokine domain of CXCL16 (Fig. 8A), and the migration was dose-dependent. The migratory response of activated PP T cells was further analyzed for a subset of chemokines that are expressed by the distinct regions of PPs. CCL19 and CXCL13 are expressed by the IFR and the follicular region of PPs, respectively (31, 32). In contrast, CCL20 is predominantly expressed by FAE in PPs (8, 9). Whereas activated CD8+ T cells selectively responded to CXCL16, activated CD4+ T cells retained chemotactic activity to CCL19, especially at a higher concentration (Fig. 8B). In contrast, both activated CD4+ and CD8+ T cells showed only a marginal migratory response to CCL20. CXCL13 slightly induced CD4+ T cell migration at a high concentration. Furthermore, the activated PP T cells selectively adhered to mCXCL16-expressing CHO cells, but not to wild-type CHO cells (Fig. 8C). These data suggest that CXCL16 plays a role in the migration and retention of activated T cells in PPs.
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We further examined the physiological role of FAE-derived CXCL16. First, we carefully examined T cell distribution in PPs by immunofluorescence staining with anti-CD3 mAb. The PP T cells were observed in three different regions of the PPs. Although the majority accumulated in the IFR, a small number of T cells were localized in the peripheral region of the mantle zone and the SED between the FAE and lymphoid follicles (Fig. 9). Some T cells were found in the interepithelial region of FAE, termed M cell pockets. In addition, a third population of T cells was observed inside lymphoid follicles, particularly in the germinal center that is formed at the serosal side of the lymphoid follicles (Fig. 9).
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0.8 (Fig. 10D). In contrast, the SED migration of T cells was markedly inhibited by the CXCL16 mAb treatment, whereas the frequency of T cells in the IFR was increased (Fig. 10, B and C). As a consequence, the SED/IFR ratio of T cell frequency was decreased to <0.2 (Fig. 10D). This observation suggests that CXCL16 is an important molecule for guiding activated T cells from the IFR to the SED in the PP microenvironment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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We demonstrated that a subpopulation of T cells isolated from PPs express CXCR6, a CXCL16 receptor. This receptor is functional because CXCL16 mediated the adhesion and migration of CXCR6+ T cells. The fact that the expression level of CXCR6 and migratory response to CXCL16 is higher in CD8+ T cells than in CD4+ T cells could reflect the difference in activation status between the two populations, because CD8+ T cells have been known to respond to Ag stimulation more rapidly than CD4+ T cells (36, 37).CXCR6 is highly up-regulated in PP and splenic T cells after in vitro stimulation (Fig. 7A) (18). CXCR6 has been defined as a marker of effector/memory T cells, because it is selectively expressed on the CD4+ T cells with the activated phenotype (17, 30). We also confirmed that CXCR6+CD4+ PP T cells mainly possess the memory phenotype (CD44highCD62Llow). In contrast, CCR7 is highly expressed on naive CD4+ and CD8+ T cells and is down-regulated in CXCR6+ effector/memory T cells in human peripheral blood (17, 30), indicating that CXCR6 expression is negatively correlated with CCR7 and CD62L expression. Because CCR7 and CD62L are thought to be lymphoid homing receptors, their down-regulation and the up-regulation of CXCR6 may enable the activated T cells to migrate into inflamed extralymphoid tissue. This possibility coincides with the observation that CXCL16 is induced in the inflamed human liver (38, 39) and the spinal cord in experimental autoimmune encephalomyelitis in mouse (28).
The constitutive expression of CXCL16 was observed not only on the FAE of PPs but also on the ILFs and the colonic patches, suggesting its homeostatic role in the inductive site of GALTs. We demonstrated three different regional distributions of T cells in PP microcompartments (Fig. 9). The major population residing in the IFR is most likely composed of CCR7+ naive T cells, because there is an abundant expression of CCR7 ligands, CCL19 and CCL21, by stromal and endothelial cells in this area (31, 32). The second population is distributed around the SED and the adjacent peripheral region of lymphoid follicles. Adoptive transfer experiments revealed that CXCR6+-activated T cells migrated into this area at a high frequency (Fig. 10). This migration into the SED was remarkably inhibited by the in vivo neutralization of CXCL16 with blocking mAb, although the total number of migrating T cells into PPs did not change. This finding suggests that CXCL16 guides the SED migration of CXCR6+CCR7lowCD62low T cells that is probably activated by mature Ag-primed DCs migrating into the IFR. However, we do not exclude the possibility that other FAE-derived chemokines such as CCL20 may likewise mediate the interaction between the FAE and T cells, because CCR6, the sole receptor of CCL20, has been reported to be expressed by subsets of memory CD4+ and CD8+ T cells (40, 41, 42). It is necessary to confirm whether this is the case in PP T cells, because in vitro activated PP T cells did not respond to CCL20, at least in the condition examined here. The SED zone accumulates external Ags sampled by M cells (43) and may therefore serve as the marginal zone where naive B cells encounter Ags and the subsequent B-T collaboration occurs. The third population of PP T cells was observed in the germinal center, which is localized beneath the mantle zone of the B cell follicles and near the serosa. This population is surmised to be follicular Th cells or germinal center Th cells observed in the human tonsil (44, 45, 46, 47, 48). These cells play a key role in B cell differentiation and Ab production. Because these cells are characterized by CXCR5+CCR7–, they are most likely attracted by BLC/CXCL13 expressed on follicular DCs and stromal cells in the B cell follicles. This hypothesis was confirmed by the observation that CXCR5-deficient T cells failed to migrate into the B cell follicles of peripheral lymph nodes (49). These findings and the results of the present study suggest that the distribution of T cells in GALT could be dependent on the orchestrated expression of three chemokine receptors: CCR7, CXCR5, and CXCR6.
Full-length CXCL16 is composed of an N-terminal chemokine domain followed by a mucin-like stalk, a transmembrane domain, and a short cytoplasmic tail (17, 18). Proteolytic cleavage is therefore an important process for CXCL16 to function as a soluble chemoattractant. The membrane-integrated protease, ADAM10, seems to be responsible for this process in fibroblasts and endothelial cells, because CXCL16 release induced by TNF- and IFN- was largely suppressed in ADAM10-deficient cells (19, 20). Although it is unclear whether this is the case for the FAE, at least ADAM10 mRNA is abundantly expressed by the FAE (our unpublished observations). We and others (14, 50) have reported that other membrane-type matrix metalloproteinases, namely, MMP-14 and MMP-15, are highly up-regulated in the FAE. These proteases might also participate in CXCL16 processing, although further study is necessary to prove this.
The basolateral plasma membrane of M cells is deeply invaginated, allowing the migration of lymphocytes and myeloid cells into the interepithelial microdomain, called M cell pockets (3). M cell pockets not only effectively shorten the distance from the apical to the basal plasma membranes of M cells but also mediate close contact between M cells and immune cells. However, the detailed mechanism of the M cell pocket formation remains unknown. Half of the lymphocytes observed in the M cell pockets are T cells in human and rat (51, 52). Interestingly, they possess the memory phenotype, as characterized by CD45RO and CD40L expression. CXCL16 mediates PP T cell adhesion in vitro (Fig. 8C). These results may indicate its potential role in T cell adhesion and retention in the M cell pockets. Taking all the data herein into consideration, we suggest that CXCL16 is an important effector molecule for mediating lympho-epithelial interaction in the inductive sites of GALT.
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Acknowledgments |
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Disclosures |
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Footnotes |
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1 This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Grants-in-Aid for Scientific Research in Priority Areas), the Naito Foundation, the Uehara Memorial Foundation, and the Mochida Memorial Foundation. 
2 Address correspondence and reprint requests to Dr. Hiroshi Ohno, Laboratory for Epithelial Immunobiology, Research Center for Allergy and Immunology, The Institute of Physical and Chemical Research (Japan), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: ohno{at}rcai.riken.jp
3 Abbreviations used in this paper: PP, Peyer’s patch; ADAM10, a disintegrin and metalloproteinase domain-10; CHO, Chinese hamster ovary; CV, conventional; DAPI, 4',6'-diamidino-2-phenylindole; DC, dendritic cell; FAE, follicle-associated epithelium; GF, germ-free; IEC, intestinal epithelial cell; IFR, interfollicular region; ILF, isolated lymphoid follicle; ISH, in situ hybridization; mCXCL16, murine CXCL16; SED, subepithelial dome; UEA-1, Ulex europaeus agglutinin-1.
Received for publication July 26, 2005. Accepted for publication September 30, 2005.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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, MIP-3
, and secondary lymphoid organ chemokine. J. Exp. Med. 191: 1381-1394. receptor signaling induces the chemokine CCL20 in intestinal epithelium. Gastroenterology 127: 213-223. [Medline] and TNF- and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J. Immunol. 172: 6362-6372. . J. Immunol. 162: 186-194. Related articles in The JI:
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) or control IgG (
). Activated T cells were prepared by in vitro stimulation with anti-CD3 and CD28 mAbs. B, CD4+ T cells were divided into CXCR6– and CXCR6+ populations and further analyzed for CD44 and CD62L expression.
) and CD8+ (•) T cells. B, chemotactic activity of activated PP CD4+ and CD8+ T cells were performed with various chemokines that are expressed in the distinct regions of PPs at the concentration of 10 (
