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The Journal of Immunology, 1998, 161: 3219-3223.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Cytokines Regulate Expression and Function of the HIV Coreceptor CXCR4 on Human Mature Dendritic Cells1

J. Paul Zoeteweij*, Hana Golding{dagger}, Howard Mostowski{ddagger} and Andrew Blauvelt2,*

* Dermatology Branch, National Cancer Institute, and Divisions of {dagger} Viral Products and {ddagger} Cell and Gene Therapy, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
HIV-infected dendritic cells (DC) efficiently transmit infection to CD4+ T cells during the process of T cell activation. To further understand interactions between DC and HIV, cytokine regulation of HIV coreceptors on cultured Langerhans cells (cLC, as prototypes of mature DC) was studied. Expression of cell surface CXCR4 on cLC was up-regulated by IL-4 and TGF-ß1 and inhibited by IFN-{alpha}, IFN-ß, and IFN-{gamma}, whereas cytokines did not appreciably regulate CCR5. Changes in cell surface CXCR4 expression on cLC correlated with T cell-tropic (X4)-HIV envelope-mediated syncytium formation and X4-HIV infection levels. A relative increase in the ratio of type 2/type 1 cytokine production, which can occur in HIV disease, may up-regulate CXCR4 expression on mature DC and promote infection by X4 viruses. Importantly, these findings suggest that cytokine dysregulation may be linked to the emergence of X4-HIV strains as HIV-infected individuals progress to AIDS.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Human immunodeficiency virus enters cells by binding to cell surface CD4 and coreceptor molecules (1, 2, 3, 4). Although the list of possible coreceptors is continuously expanding, the major coreceptors are CCR5 and CXCR4, facilitating cell entry of macrophage-tropic (R5) and T cell-tropic (X4) viruses, respectively. RANTES, macrophage-inflammatory protein-1{alpha}, and macrophage-inflammatory protein-1ß are ligands for CCR5 and block R5-HIV infection, whereas stromal cell-derived factor-1 (SDF-1)3 is a ligand for CXCR4 and blocks X4-HIV infection. Genetic studies on chemokine receptors and their ligands point to the importance of these molecules in the pathogenesis of HIV disease (5, 6, 7). Currently, additional factors that may regulate HIV coreceptor expression and function are the focus of many research teams.

Dendritic cells (DC) are potent activators of both MHC class I- and MHC class II-restricted Ag-specific T cells (8), and in vitro studies have shown that HIV is efficiently transmitted from DC to CD4+ T cells during this process (9, 10). Furthermore, it is believed that DC originating from epithelial surfaces (i.e., Langerhans cells (LC)) play a major role in establishing HIV infection in lymph node T cell populations (11, 12), a major site of HIV replication (13, 14). As shown in this report, specific cytokines modulate expression and function of specific HIV cell surface receptors on cultured LC (cLC) (as prototypes of mature DC). Our findings suggest that cytokine dysregulation may contribute to the emergence of X4-virus strains in advanced stages of HIV disease.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell isolation and culture conditions

This study was approved by the Institutional Review Board of the National Cancer Institute. As described previously (15), blisters were induced on clinically normal skin of healthy volunteers, and epidermal cell suspensions were prepared by limited trypsinization of blister roofs (i.e., epidermal sheets). On average, 20 blisters from 1 volunteer yielded 50 x 106 cells containing 2 to 3% LC. Cells were cultured in RPMI 1640 (Life Technologies, Gaithersburg, MD) containing 10% human AB+ serum (Advanced Biotechnologies, Columbia, MD), 2 mM L-glutamine (Life Technologies), 100 U/ml penicillin (Life Technologies), 100 µg/ml streptomycin (Life Technologies), and 5 x 10-5 M 2-ME (Sigma Chemical, St. Louis, MO). After 2 days of culture, 10 to 15 x 106 cells were recovered as nonadherent viable cells, containing 4 to 12% LC. For some experiments, epidermal sheets were directly placed into culture without trypsinization (RPMI containing 20% human AB+ serum) and LC spontaneously migrated into the medium during culture. For other experiments, fresh epidermal cell suspensions were incubated with FITC-conjugated anti-CD1a mAb, and LC were positively selected by cell sorting. Epidermal cells or sheets were cultured for 48 h in the presence or absence of exogenous cytokines, and for some experiments in the presence of neutralizing polyclonal Abs (pAb) directed against IFN-{gamma} (10 µg/ml) or TGF-ß1 (1 µg/ml). Recombinant human TNF-{alpha}, TGF-ß1, IFN-{gamma}, IL-1{alpha}, IL-1ß, IL-4, IL-6, IL-10, IL-12, IL-15, and neutralizing Abs were purchased from R&D Systems (Minneapolis, MN), IFN-{alpha} and IL-16 from Endogen (Woburn, MA), GM-CSF from Immunex (Seattle, WA), IFN-ß from Life Technologies, and IL-2 from Chiron (Emeryville, CA).

Analysis of cell surface molecules by flow cytometry

After incubation, cells were harvested, washed with cold PBS, resuspended in PBS containing 0.1% (w/v) BSA and 0.05% (w/v) NaN3, and transferred to V-bottom 96-well plates (2 x 105 cells/well). For analysis of CCR5 and CXCR4, cells were preincubated with human IgG (100 µg/ml) for 30 min, washed twice, and incubated with rabbit pAbs generated against CCR5 or CXCR4 at 10 µg/ml (12), or with a mouse mAb directed against CXCR4 (12G5; PharMingen, San Diego, CA) for 60 min at 4°C. Cells were washed twice and incubated with biotinylated goat anti-rabbit IgG or biotinylated goat anti-mouse IgG for 45 min at 4°C (Caltag Laboratories, San Francisco, CA), followed by phycoerythrin (PE)-labeled streptavidin for 30 min at 4°C (Life Technologies). During the conjugation with streptavidin, cells were stained with FITC-labeled CD1a mAb (Ortho Diagnostics Systems, Raritan, NJ). In parallel experiments, cells were directly double stained with FITC-labeled CD1a and PE-conjugated CD4 mAbs (PharMingen) or PE-labeled CD1a and FITC-DR (PharMingen). After addition of propidium iodide (5 µg/ml), cells were analyzed for fluorescence on a FACScan flow cytometer (Becton Dickinson, Mountain View, CA) using three-color analysis. Dead cells were identified by propidium iodide fluorescence and excluded from further analyses.

HIV coreceptor fusion assay

Sensitive fusion assays were used to detect the ability of CCR5 and CXCR4 expressed on cLC to fuse with HIV envelope-expressing cells (12). Briefly, syncytium formation was measured 8 and 18 h after coculture of target cells (LC isolated by cell sorting or spontaneous migration from epidermal sheets) with HIV envelope-expressing effector cells at a 1:1 ratio in a 96-well plate (25,000 cells/well). PM1 cells, which express CCR5 and CXCR4, served as positive controls (data not shown). As effector cells, CD4-12E1 cells were infected with either vaccinia recombinants expressing HIV-1 IIIB (X4) or JR-FL (R5) envelopes (12).

HIV infection assay

Epidermal cells cultured for 2 days were washed and replated in 12-well plates at a density of 2 x 106 cells/well. Cells were infected with HIV-1 IIIB (Advanced Biotechnologies, at a multiplicity of infection of 0.5–1) for 4 h, washed three times with PBS, incubated for 10 min at 37°C with PBS containing 0.25% (w/v) trypsin to remove extracellular attached virus (9, 16), and washed twice with Hanks’ buffer. Cellular DNA was extracted using the Qiamp Blood Kit (Qiagen, Chatsworth, CA) and DNA was quantified by spectrophotometry. Of note, viral stocks were treated before use with RNase-free DNase 1 (Boehringer, Indianapolis, IN) to remove contaminating DNA.

Total DNA (0.35 µg) was examined for HIV DNA using semiquantitative PCR and Southern blot analyses. The following primer sets (Genosys Biotechnologies, The Woodlands, TX) were designed based on previously published sequences (17): 5'-primer, 5'-GGCTRRCTAGGRAACCCACTG; 3'-primer, 5'-CTGCTAGAGATTTTCCACA. These primers were designed to detect early HIV transcripts (16, 17). Denaturation was performed for 1 min at 95°C, annealing for 1 min at 45°C, and extension for 2 min at 72°C for 32 cycles. DNA from PHA-stimulated PBMC infected with HIV, or commercially available HIV DNA (Advanced Biotechnologies), were used as positive PCR controls (data not shown). The quality of the DNA was controlled by amplification of ß-globin-specific sequences, using primers as previously published (18). Twenty microliters of the PCR product were electrophoresed in 2% (w/v) agarose gels. After transfer to nylon membranes, HIV-specific bands were radiolabeled with a 32P-labeled probe (5'-CTGTTGTGTGACTCTGGTAACTAGAGATCC) against an internal sequence of the HIV PCR product and analyzed after exposure to film. ß-Globin PCR products were visualized under UV light after staining of agarose gels with ethidium bromide.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
cLC express CXCR4, CCR5, and CD4

By flow cytometry, LC were readily identified within epidermal cell suspensions by their characteristic expression of CD1a and HLA-DR (Fig. 1GoA). Next, cells were double-labeled with CD1a and coreceptor-specific Abs. Cell surface CD4 is degraded during trypsinization of epidermal sheets but was subsequently reexpressed after 2 days of culture (Fig. 1GoB). CD1a+ cLC also expressed significant levels of CXCR4 and CCR5 (Fig. 1Go, C and D). Cells cultured for 4 days maintained expression of the chemokine receptors. All CXCR4 expression data obtained with the CXCR4 pAb were confirmed with CXCR4 mAb (12G5). However, a recently available anti-CCR5 mAb (2D7; PharMingen) stained LC less well than CCR5 pAb and thus did not provide useful data for this study.



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  		FIGURE 1. Cultured LC express surface CD4 and HIV coreceptors. LC were isolated from normal skin of healthy volunteers, cultured for 2 days, and examined for surface phenotype by Ab labeling and flow cytometry. Cultured LC were easily identified in epidermal cell cultures by expression of CD1a (y-axis) and HLA-DR (x-axis) (A); CD1a+ cells were gated and examined for CD4 (B, shaded curve), CXCR4 (C, E, F, shaded curves), or CCR5 (D, shaded curve) expression; CXCR4 expression after incubation with IFN-{gamma} (E, bold line) or TGF-ß1 (F, bold line). Preimmune sera (for pAbs) or isotype control Abs (for mAbs) were used as negative controls for all experiments (B-F, solid lines).

 
Cytokine regulation of CXCR4, CCR5, and CD4 expression on cLC

To study the effects of cytokines on HIV coreceptor expression, a wide panel of cytokines were added at a dose of 20 ng/ml (unless otherwise indicated) into the medium at day 0. After 24 h, a second similar dose of cytokine was added. Interference by endogenously produced cytokines in this culture system was not likely, since sensitive ELISA (detection limit usually 20 pg/ml) failed to detect endogenously produced IL-1{alpha}, IL-1ß, IL-4, IL-5, IL-6, IL-10, IL-12, IFN-{gamma}, TNF-{alpha}, or GM-CSF during culture. Cells cultured for 2 days were examined for coreceptor expression as described above. IFN-{alpha}, IFN-ß, and IFN-{gamma} reduced expression of CXCR4 by 60 to 80% (Table IGo, Fig. 1GoE, Fig. 2GoA). Other proinflammatory cytokines only slightly decreased CXCR4 expression. By sharp contrast, IL-4 and TGF-ß1 up-regulated CXCR4 expression by 40% and 70%, respectively (Table IGo, Fig. 1GoF, Fig. 2GoB). Similar effects on CXCR4 expression were found with 1) cells cultured for longer time periods (up to 4 days) or 2) cells that migrated out of intact epidermal sheets, which excluded trypsinization of epidermal sheets (data not shown). The cytokine-induced effects on CXCR4 expression were concentration dependent (Fig. 2Go). In the presence of neutralizing Abs against IFN-{gamma} or TGF-ß1, IFN-{gamma} or TGF-ß1, respectively, did not induce changes in CXCR4 expression (not shown). Finally, CXCR4 expression on LC was also down-regulated by 200 nM SDF-1ß (not shown), similar to recent reports in other cell types (19). CCR5 expression was only minimally affected by any of the cytokines tested (Table IGo). Reexpression of CD4 was also suppressed by every type of IFN (Table IGo). Doses of cytokines 10-fold higher (i.e., 200 ng/ml) did not appreciably affect the results as listed in Table IGo. Only low doses (<0.2 ng/ml) of IL-6 and IL-10 were studied, because marked depletion of CD1a+ LC was observed at higher doses (>50% depletion). IL-10 induced depletion of LC may be due to apoptosis, as has been reported previously (20), whereas this is the first observation of LC depletion by IL-6. To assure that the cytokine-induced changes in CXCR4 expression were not due to similar changes in DC maturation, cLC surface expression levels of costimulatory and HLA molecules were determined and shown to be similar (with TGF-ß1) or higher (with IFN-{gamma} or IL-4) on LC compared with control LC (not shown).


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  		Table I. Surface expression of CXCR4, CCR5, and CD4 on LC after a 2-day incubation with various cytokines1

 


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  		FIGURE 2. IFN-{gamma} down-regulates, whereas IL-4 and TGF-ß1 up-regulate, surface expression of CXCR4 on cultured LC in a dose-dependent manner. Freshly isolated LC were cultured for 2 days in the presence or absence of cytokines in doses as indicated. CD1a+ cells were examined for surface CXCR4 expression by Ab labeling and flow cytometry. Nonspecific staining with preimmune rabbit sera or isotype control Abs were subtracted from CXCR4 staining in all cases. Data represent the mean fluorescence intensities of cytokine-treated cells compared with mean fluorescence intensities of cells incubated in medium alone (control); A, IFN-{gamma}, #, p < 0.01, *, p < 0.001; B, IL-4 (•) and TGF-ß1 ({blacktriangleup}), #, p < 0.02, *, p < 0.001; Data represent means ± SEM of at least three independent experiments.

 
Cytokine-induced changes in LC CXCR4 expression correlate with changes in X4-HIV envelope syncytium formation and X4-HIV infection

To determine whether surface coreceptor expression correlated with functional activity, the ability of mature LC to fuse with HIV envelope-expressing effector cells was investigated. For this purpose, pure LC populations (>90%) were obtained either by cell sorting or by culturing intact epidermal sheets for 2 days and collecting emigrated LC from the medium. Mature LC fused with R5- and X4-HIV envelope-bearing cells (Fig. 3Go). When cultured in the presence of IFN-{gamma}, a potent inhibitor of CXCR4 expression (Fig. 2GoA), fusion of LC with X4 envelopes was strongly reduced. TGF-ß1, a potent inducer of CXCR4 expression (Fig. 2GoB), increased fusion with X4 envelopes (Fig. 3Go). Consistent with the relative inability of cytokines to regulate CCR5 expression, fusion of LC with R5 envelopes was not changed by IFN-{gamma} or TGF-ß1. Furthermore, IFN-{gamma} decreased and TGF-ß1 increased X4-HIV infection using an assay able to detect early HIV transcripts (Fig. 4Go). To confirm that HIV specifically infected LC within epidermal cell suspensions, ~90% of LC were removed by immunomagnetic bead separation as previously described (21). Few HIV transcripts were detected in LC-depleted epidermal cell suspensions (Fig. 4Go). As further controls, SDF-1ß, the ligand for CXCR4, blocked infection of LC by X4-HIV, whereas RANTES, a ligand for CCR5, had no effect on X4-HIV infection of LC (Fig. 4Go).



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  		FIGURE 3. IFN-{gamma} decreases and TGF-ß1 increases fusion between cultured LC and effector cells bearing X4-HIV envelopes. LC were purified by allowing the cells to spontaneously emigrate from epidermal sheets for 2 days in the presence or absence of cytokines. LC were then cocultured with effector cells expressing either X4-HIV envelopes (HIV IIIB) or R5-HIV envelopes (JR-FL), and syncytia were counted 8 h later. The number of syncytia obtained with LC cultured in the presence of 20 ng/ml of IFN-{gamma} or TGF-ß1 were compared with the number of syncytia obtained with control (C) LC cultured in media alone. Similar results were obtained using LC purified by cell sorting (not shown). The absolute numbers of syncytia per well observed with control LC ranged from 20 to 30 for R5-HIV envelope-expressing cells, and from 25–135 for X4-HIV envelope-expressing cells. Data represent means ± SEM of four independent experiments. *, p < 0.001.

 


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  		FIGURE 4. IFN-{gamma} decreases and TGF-ß1 increases X4-HIV entry into cultured LC. LC, cultured for 2 days in the presence or absence of cytokines, were exposed to HIV IIIB for 4 h. The cells were then washed and trypsinized, and DNA was extracted and examined for the presence of early (latent) HIV transcripts (R/U5), or ß-globin as controls, by semiquantitative PCR and Southern hybridization. In some experiments, CD1a+ LC were depleted (LC depleted) before infection (n = 2), chemokines at 200 nM were added 30 min before infection (n = 3), or LC were cultured in the presence of 20 ng/ml cytokines as indicated (n = 4). Control, LC cultured in medium alone; NI, noninfected cells). The data shown are representative.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Cell surface CXCR4 is a major determinant for HIV infection by X4 viruses. In this report, cytokines were shown to regulate cell surface CXCR4 on mature DC, a key target cell in HIV-infected individuals. Specifically, IFNs reduced CXCR4 expression, while TGF-ß1 and IL-4 up-regulated CXCR4 expression. Cytokine-induced changes in CXCR4 expression correlated with X4 infection and X4 envelope-mediated syncytium formation.

The biochemical pathways underlying regulation of CXCR4 expression are unknown. A sequence with homology to the IFN response element is located in a region containing CXCR4 gene promoter activity (22), implying possible transcriptional regulation. Furthermore, CXCR4 can be rapidly down-regulated by phorbol esters and SDF-1 as shown here and by others (19). In T cells, CXCR4 can be rapidly induced (albeit transiently) by IL-2 (23). Similarly, activation (=maturation) of immature DC (i.e., freshly isolated LC) causes a rapid up-regulation of CXCR4 (12). Taken together, these findings suggest that CXCR4 on HIV target cells is highly sensitive to extracellular stimuli. By contrast, in our studies cytokines did not appreciably alter cell surface CCR5 expression and function on mature DC. In T cells, IL-2 induced a very slow increase in CCR5 expression (23), whereas IL-10 has been shown recently to up-regulate CCR5 expression in monocytes (24).

When HIV-infected individuals progress to AIDS, changes in blood cytokine and lymphoid cytokine profiles can occur. Specifically, IFN-{gamma} production is impaired (favoring type 2 immune responses) and TGF-ß1 levels are elevated (25, 26, 27, 28). Concomitantly, the onset of AIDS correlates with an expansion of the viral phenotype from solely R5 viruses to a combination of R5 and X4 viruses (29, 30, 31). Based on our studies, impaired IFN-{gamma} and/or enhanced IL-4/TGF-ß1 production may favor increased expression of CXCR4 on DC and subsequent DC infection with X4 virus. Recent results show that IL-4 also increases CXCR4 expression on PBMC, promoting X4 viral infection of these cells (32).

In summary, some type 2 cytokines increased, whereas some type 1 cytokines decreased CXCR4 expression and function on mature DC generated from human skin. Understanding regulation of HIV entry into DC may be critical in understanding HIV infection and depletion of T cells, since HIV-infected DC efficiently promote infection of T cells during the process of Ag-specific immune activation. Finally, these findings support the hypothesis that cytokine dysregulation, as can occur in HIV disease, may contribute to the emergence of cytopathic HIV strains, providing a link between immunologic and virologic correlates of HIV disease progression.


   Acknowledgments
 
We thank Inga Tokar for assisting with the healthy volunteers; Jody Manischewitz, Sandra S. Cohen, Vera Klaus-Kovtun, and Sharon T. Eyes for expert technical assistance; Harry Schaefer for preparation of the figures; and Gene M. Shearer and Mark C. Udey for review of the manuscript.


   Footnotes
 
1 This work was partially supported by a grant from the Office of Women Health, Food and Drug Administration. Back

2 Address correspondence and reprint requests to Dr. Andrew Blauvelt, Building 10/Room 12N238, 10 Center Dr. MSC 1908, Bethesda, MD 20892-1908. E-mail address: Back

3 Abbreviations used in this paper: SDF-1, stromal cell-derived factor-1; DC, dendritic cells; LC, Langerhans cells; cLC, cultured Langerhans cells; pAb, polyclonal Abs; PE, phycoerythrin. Back

Received for publication June 1, 1998. Accepted for publication August 5, 1998.


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 Materials and Methods
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