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The Journal of Immunology, 2001, 167: 4791-4795.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: CCR4 Mediates Antigen-Primed T Cell Binding to Activated Dendritic Cells

Meng-tse Wu, Hui Fang and Sam T. Hwang1

Dermatology Branch, National Cancer Institute, Bethesda, MD 20892


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The binding of a T cell to an Ag-laden dendritic cell (DC) is a critical step of the acquired immune response. Herein, we address whether a DC-produced chemokine can induce the arrest of T cells on DC under dynamic flow conditions. Ag-primed T cells and a T cell line were observed to rapidly (~0.5 s) bind to immobilized DC at low shear stress (0.1–0.2 dynes/cm2) in a pertussis toxin-sensitive fashion. Quantitatively, Ag-primed T cells displayed 2- to 3-fold enhanced binding to DC compared with unprimed T cells (p < 0.01). In contrast to naive T cells, primed T cell arrest was largely inhibited by pertussis toxin, neutralization of the CC chemokine, macrophage-derived chemokine (CCL22), or by desensitization of the CCL22 receptor, CCR4. Our results demonstrate that DC-derived CCL22 induces rapid binding of activated T cells under dynamic conditions and that Ag-primed and naive T cells fundamentally differ with respect to chemokine-dependent binding to DC.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
T cell activation by APCs such as macrophages, B cells, and dendritic cells (DC)2 is critical to the development of the acquired immune response (1). Such activation occurs (2) through the development of an intricate assembly of adhesion and signaling molecules at the interface of the APC and T cell termed the "immunological synapse" (3) or supramolecular activation cluster (4). In order for the immunological synapse to form, the T cell must transition from a migratory to a stationary state. Adhesive interactions between the T cell and DC, in part stimulated by engagement of the TCR (5, 6), have been reported to be mediated by several adhesion molecules and their corresponding receptors, which include LFA-1/ICAM-1,-2, -3, CD2/LFA-3, and DC-SIGN/ICAM-3 (7, 8, 9, 10).

T cells may potentially interact with DC at several distinct sites. Naive as well as a central memory subset of T cells (11), both characterized by expression of CD62L (L-selectin) and CCR7, recirculate through lymph nodes (LN) and interact with Ag-bearing DC. In the periphery, activated, Ag-bearing DC may bind to cognate effector memory T cells (mTC). In organ culture, mTC-DC conjugates have been observed to emigrate from skin of healthy donors (12) and can be found in afferent lymph as well (13).

Chemokines represent a growing family of chemoattractant proteins that bind to G protein-coupled (pertussis toxin-sensitive) transmembrane receptors (14). It has been shown that activated DC may secrete a variety of chemokines (15), including the CCR4 ligands: CCL22/macrophage-derived chemokine (MDC) (16, 17), and CCL17/thymus and activation-regulated chemokine (TARC) (18, 19). Furthermore, both CCL22 and CCL17 have been shown to attract Ag-activated (but not naive) T cells in chemotaxis assays in vitro (18, 20). Although integrins appear to be important for T cell-DC binding, integrins normally are found in an inactive binding state, but can be triggered by chemokines to increase both affinity and avidity for ligands such as ICAM-1 (21). Therefore, we hypothesized that DC-produced chemokines may play critical roles in DC-T cell binding.

To test this hypothesis, we immobilized DC to the floor of a parallel plate flow chamber, introduced T cells under low shear stress, and observed the rapid binding of T cells to DC under conditions that could distinguish durable, shear-resistant adhesion from transient juxtaposition. In contrast to the binding of naive T cells to DC, the binding of Ag-primed T cells to DC was sensitive to pertussis toxin (PTX) and mediated by CCR4. Thus, chemokine-mediated binding demonstrated by primed T cells may represent a selective mechanism for allowing Ag-bearing APC to preferentially engage activated (or memory) vs naive T cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Reagents, animals, cell lines

Recombinant murine chemokines/cytokines were purchased from PeproTech (Rocky Hill, NJ) unless otherwise specified. Anti-murine CCL22, CXCL13, and CCL11 Abs (all neutralizing, affinity-purified goat IgG) were purchased from R&D Systems (Minneapolis, MN).

BALB/c and DO11.10 (OVA peptide 323–339-specific) TCR-transgenic mice on a BALB/c background (22) (The Jackson Laboratory, Bar Harbor, ME) were used in institutionally approved protocols. The T cell hybridoma cell line, B 9.1, is specific for the MHC II-restricted, immunodominant hen egg-white lysozyme (HEL) peptide 103–117 (23). BALB/c bone marrow-derived DC (BMDC) were generated as described (24) and cultured in complete medium with RPMI 1640, 5% FCS, IL-4 (10 ng/ml), GM-CSF (10 ng/ml), and Flt3 ligand (R&D Systems). BMDC were used on day 9–12 when >83% of nonadherent cells expressed CD11c, CD40, CD80, CD86, and I-Ad by flow cytometry. BMDC showed a 6-fold response to CCL21 vs PBS in chemotaxis assays and no response to CCL5. Real-time quantitative RT-PCR was performed as described (25).

In vivo-enriched OVA-primed T cells were generated by s.c. immunizing DO11.10-transgenic mice with OVA peptide 323–339 (200 µg per mouse) in CFA. Five to 7 days after the immunization, cells from enlarged draining LN were pooled and depleted of CD19+ and CD40+ cells by immunomagnetic bead depletion. Naive OVA-specific T cells were isolated from LN and spleen of DO11.10 mice by identical depletion methods. After selection, the resulting cells were ~97% CD3e+ cells and ~82% CD4+ cells by flow cytometric analysis.

In vitro flow arrest assay

For immobilization of BMDC, a droplet of anti-mouse CD40 (HM40-3, 10 µg/ml in 100 µl PBS; BD PharMingen, San Diego, CA) was first centrally applied to 35-mm plastic dishes at 4°C overnight and then blocked with PBS/1% BSA for 45 min at 25°C. Day 9–12 BMDC (1 x 106/ml, 100 µl for each dish) were then applied to the anti-CD40-coated plates for 2.5 h at 4°C. For quantitative analysis of T cell arrest, B 9.1 cells and T cells were labeled with calcein-AM (Molecular Probes, Eugene, OR) and exposed to different reagents as indicated: chemokines (25 ng/ml for 30 min at 37°C), anti-chemokines Abs (ant-CCL11, anti-CCL22, and anti-CXCL13 at 2.5 µg/ml for 5 min before flow experiments at 20°C), and PTX (100 ng/ml for 2 h at 37°C; Calbiochem, La Jolla, CA). T cells (1 x 106/ml) were resuspended into a 12-ml syringe and introduced into a parallel plate flow chamber (Glycotech, Rockville, MD) that was affixed to the dish containing immobilized DC. Flow was adjusted to shear stresses of 0.2 (for B 9.1 cells) and 0.1 dynes/cm2 (for DO11.10-derived T cells). Four min after cells entered the chamber, a series of eight images from randomly selected fields (1.18 mm2/field) in different quadrants of the dish were video-captured using a x4 objective under fluorescent illumination. Calcein-labeled T cells that arrested on the BMDC layer generated bright, single-cell images and were quantified using NIH Image 1.62 and expressed as the mean number of arrested cells per field ± SD. Statistical significance was calculated using a two-sided, Student’s t test. All experiments were performed a minimum of three times with similar results.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
We found that the T cell hybridoma line, B 9.1, responded to CCL22 in chemotaxis assays with maximal migration (9-fold over control) occurring between 25 and 100 ng/ml CCL22 (data not shown). By real-time, quantitative RT-PCR, cultured day 11 BMDC expressed levels of mRNA for CCL22 that were at least 1000-fold greater than for CCL21, CXCL12, CXCL13, and CCL19. CCL3 and CCL5 mRNA were expressed at slightly higher, but comparable, levels to CCL22. Supernatants from activated BMDC were effective in stimulating the chemotactic migration of B 9.1 cells in vitro, which could be blocked by >90% with desensitization of CCR4 in the presence of CCL22.

To determine whether chemokines were involved in the binding of T cells and DC, we developed a dynamic, flow chamber-based assay to measure and record the interactions of B 9.1 cells with activated DC. We took advantage of a parallel plate flow chamber system in which CD40-expressing DC were immobilized to the surface of a plastic culture dish that was precoated with anti-CD40 mAbs. B 9.1 cells were then introduced into the narrow confines of the flow chamber under defined shear stress. Arrest of the B 9.1 cells to the BMDC was rapid and occurred in <0.5 s. Some interactions were transient (lasting <4 s), while others were of longer duration (>10 s). As shown in Fig. 1GoA, many adherent cells were noted at 0.2 dynes/cm2, whereas binding was virtually abolished at shear stresses of 0.5 dynes/cm2 or above. B 9.1 cells that arrested remained attached to DC for as long as 12 min, which was the longest period of time for which we followed B 9.1 cell binding. B 9.1 cell binding to activated, skin-derived migratory DC (26) under identical conditions was quantitatively similar to that observed with BMDC, suggesting that B 9.1 cells also bound to bona fide DC that were not derived from in vitro-cultured cells.



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  		FIGURE 1. B 9.1 cells bind to activated BMDC under dynamic conditions. A, Calcein-labeled B 9.1 cells were introduced into a parallel plate flow chamber at the indicated shear stress in which activated DC were immobilized to the floor of the chamber. Cells bound to DC were quantified as described in Materials and Methods. B, B 9.1 cells were either untreated or pretreated with function-blocking anti-CD18 mAb. Anti-CD54 mAb was used to pretreat DC for 30 min before the flow assay in addition to anti-CD18 mAb treatment of B 9.1 cells in one condition.

 
Arrested cells were uniformly distributed across the surface of the flow plate, suggesting that arrest was not the result of cumulative interactions of cells with DC during the transit time across the plate (data not shown). B 9.1 cells showed no expression of CD40 by flow cytometry and did not arrest on anti-CD40-immobilized LN B cells, demonstrating that B 9.1 cell binding was specific for DC and was not the result of artifactual binding to anti-CD40 mAb. Immobilization of DC could also be performed with anti-CD80 or -CD86 mAb without affecting the numbers of B 9.1 cells arrested (data not shown). Pretreatment of B 9.1 cells with anti-CD18 mAb reduced arrest by ~80%, while combination treatment of B 9.1 cells with anti-CD18 mAb and DC with anti-CD54 mAb resulted in >95% loss of arrest (Fig. 1GoB). B 9.1 cell arrest was dependent on Golgi-mediated transport because arrest was inhibited by 80% when DC were pretreated with brefeldin A (data not shown).

The rapidity of adherence of the B 9.1 cells to BMDC suggested that a chemokine receptor-mediated process may be involved, a hypothesis that was strengthened by the observation that PTX significantly reduced arrest by ~90% (Fig. 2GoA). To determine whether B 9.1 adhesion to BMDC was mediated by a chemokine or chemokines, we desensitized specific chemokine receptors on B 9.1 cells by treating them with saturating concentrations of their known chemokine ligands (27, 28). While pretreatment with CCL5 (RANTES), CXCL10 (IFN-{gamma}-inducible protein-10), and macrophage inflammatory protein-2 had no significant effect on arrest of B 9.1 cells (Fig. 2GoA), ~90% of adherence of B 9.1 to BMDC could be blocked by pretreatment with CCL22. CCL17 (TARC), the other known ligand for CCR4, also blocked B 9.1 cell binding to BMDC (data not shown). Moreover, neutralizing anti-CCL22, but not a species-matched anti-CXCL13, Ab prevented the arrest of B 9.1 cells (Fig. 2GoB). Thus, the arrest of the B 9.1 T cells to BMDC required CCR4 and one of its ligands, CCL22.



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  		FIGURE 2. CCL22 is essential for B 9.1 cell arrest on activated BMDC. A, B 9.1 cells were pretreated with the indicated chemokines or PTX as described in Materials and Methods before initiation of the flow assay. *, p < 0.005 vs untreated (n = 8). B, The indicated anti-chemokine Abs were added to the buffer containing the B 9.1 cells at 2.5 µg/ml just before introduction of the cells into the flow chamber. C, DC, with and without overnight exposure to HEL, were immobilized to the floor of the flow chamber before the initiation of the flow of B 9.1 at three different concentrations (1.0, 0.6, and 0.15 x 106 cells/ml) at a uniform shear stress of 0.2 dynes/cm2. p = 0.001 for HEL-pulsed vs nonpulsed DC at a washing shear stress of 1.5 D (dynes/cm2) with 0.6 x 106 cell/ml flowing into the chamber (n = 3).

 
To determine whether the binding of B 9.1 cells to DC was resistant to shear stress or was altered when the DC were pulsed with HEL Ag, we allowed B 9.1 cells to bind to DC that were either not pulsed or pulsed overnight with HEL protein. Once bound, B 9.1 cells were resistant to detachment from DC by shear stresses of up to 10 dynes/cm2. Interestingly, there were consistently 30–50% more B 9.1 cells bound to pulsed compared with nonpulsed DC (Fig. 2GoC). Thus, B 9.1 cells bound to DC in a shear-dependent manner that was CD18/CD54 dependent. Once bound, B 9.1 cells were resistant to detachment by exposure to high shear stress. Finally, although not Ag dependent, the presence of Ag on the DC increased the number of cells arresting on BMDC.

To address whether in vivo-derived T cells would arrest on activated DC in a manner similar to the B 9.1 T cell hybridoma cells, we used the DO11.10 TCR-transgenic mouse, which predominantly expresses a TCR that binds to OVA peptide 323–339 in context with H2 (22). Because Ag-primed, but not naive, T cells from DO11.10 mice are responsive to CCL22 (18, 20), we activated DO11.10 T cells by immunizing mice with OVA peptide 323–339 in CFA. Activation was observed as L-selectin (CD62L) decreased from 92% expression in naive LN T cells (nTC) to 12% in Ag-primed T cells. In addition, primed T cells showed a reciprocal increase in expression of the CD44 activation marker (data not shown). As recorded under real-time conditions,3 primed DO11.10 T cells bound to immobilized BMDC under low shear stress conditions (Fig. 3Go).



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  		FIGURE 3. Arrest of primed T cells on immobilized BMDC underdynamic conditions. Ag-primed T cells isolated from OVA-immunized DO11.10 mice were introduced into a parallel plate flow chamber containing immobilized BMDC. In the upper left frame (2.558 s after initiation of video capture), a white primed T cell (indicated by the large arrow) is approaching an immobilized DC (small arrowhead). At 2.992 s, the primed T cell has just touched the boundary of the DC and by 3.426 s (lower left frame) has stopped forward progression and remains in the same position at 9.566 s (lower right frame).

 
We then introduced either primed T cells or nTC into the flow chamber that contained immobilized BMDC that either had or had not been pulsed with OVA peptide. Naive T cells were able to arrest on BMDC, but, as shown in Fig. 4Go, A and B, there was 2- to 3-fold greater binding of primed T cells to BMDC. Arrest of primed T cells (but not nTC) could be blocked by the presence of anti-CCL22 neutralizing Abs (Fig. 4GoA) or by pretreatment of primed T cells with CCL22 (Fig. 4GoB). As was also observed with B 9.1 cells, primed T cell arrest was ~50% greater when exposed to Ag-pulsed vs nonpulsed DC. Thus, in contrast with nTC, primed T cells bound to BMDC in a manner that was highly sensitive to PTX and dependent on CCL22. Furthermore, the binding of primed T cells to DC was enhanced by the presence of cognate Ag present on the DC.



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  		FIGURE 4. Arrest of primed T cells on activated BMDC is enhanced by the presence of cognate Ag and is CCL22 dependent. A, Primed T cells (PTC) and nTC (NTC) in buffer containing the indicated neutralizing anti-chemokine Abs (at 2.5 µg/ml) were introduced into the flow chamber containing OVA-pulsed (OVADC) or nonpulsed (DC) immobilized DC under conditions similar to those indicated in Fig. 2Go. At the end of the arrest assay, arrested cells were quantified as described in Materials and Methods. B, Primed T cells and nTC were pretreated with chemokines as described in Materials and Methods before the start of the arrest assay on OVA-pulsed or nonpulsed DC. n = 8 fields per condition for p value calculations.

 
Ours is the first study to demonstrate that a chemokine mediates the binding of a T cell to a DC. In the periphery, DC-mTC conjugates may play a role in delayed-type hypersensitivity responses where DC have been observed juxtaposed to lymphocytes (29). In addition, DC-mTC conjugates from skin can increase productive infection with HIV-1 (12). In the LN, recirculating CD62L+CCR7+ mTC may engage Ag-bearing DC arriving from the periphery, possibly leading to expansion of activated effector mTC (11). In contrast to previous studies of the interaction between DC and T cell in culture that used either liquid cultures (30) or a collagen matrix (31), T cells in our system interacted with DC under conditions in which tight binding could be distinguished from juxtaposition. The stringency of our system and the ability to easily quantify adhesive events permitted us to dissect the molecular mechanisms of binding using pharmacologic agents and neutralizing Abs.

There is evidence that another CCR4 ligand, CCL17/TARC, may be produced by subsets of DC (20), although TARC mRNA was only detectable in 14% of cultured murine BMDC (18). However, we cannot exclude the possibility that CCL17 may also play a similar role under other conditions. Furthermore, we cannot exclude that other adhesion mechanisms may play a role in DC-T cell binding under less stringent conditions. Certainly, nTC can interact with DC as elegantly demonstrated by Ingulli et al. (32). It is possible that DC adhere to naive T cells via other means such as the DC-SIGN/ICAM-3 pathway of adhesion that has been shown to be important for resting, but not activated, T cell binding to DC (10). Given the low probability that any naive T cell has the correct receptor for an Ag presented by DC, the lower binding efficiency may actually facilitate rapid sampling and prevent DC from being literally "covered" with noncognate nTC for long periods of time. It would be interesting to determine which chemokines, if any, are of critical importance in the binding of nTC to DC.

The interaction of a DC with a T cell plays a critical role in the initiation and regulation of the acquired immune response. Although activated DC produce several chemokines, we find that lasting adhesive interaction between Ag-primed T cells and DC requires CCL22 and CCR4 in our experimental system. The presence of cognate Ag on the DC appears to strengthen this interaction, although this is not required for adhesion to take place. Thus, CCL22 may make it possible for DC to efficiently engage activated (or memory) T cells to enhance (or reactivate) immune responses with a corresponding increase in effector function.


   Acknowledgments
 
We thank Drs. Scott I. Simon and Joost J. Oppenheim for helpful discussions and comments, Dr. Stephen I. Katz and Dr. Atsushi Sato for providing DO11.10 mice, and Erik Gonzalez and David Fitzhugh for technical assistance.


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Sam T. Hwang, Dermatology Branch, National Cancer Institute, Building 10, Room 12N246, 10 Center Drive, Bethesda, MD 20892-1908. E-mail address: hwangs{at}mail.nih.gov Back

2 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; BMDC, bone marrow-derived DC; mTC, memory T cell; nTC, naive T cell; MDC, macrophage-derived chemokine; TARC, thymus and activation-regulated chemokine; PTX, pertussis toxin; HEL, hen egg-white lysozyme. Back

3 The on-line version of this article contains supplemental material. Back

Received for publication July 30, 2001. Accepted for publication September 4, 2001.


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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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