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Originally published online as doi:10.1189/jlb.0204106 on June 3, 2004

Published online before print June 3, 2004
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(Journal of Leukocyte Biology. 2004;76:603-608.)
© 2004 by Society for Leukocyte Biology

Immobilization of rolling NK cells on platelet-borne P-selectin under flow by proinflammatory stimuli, interleukin-12, and leukotriene B4

S. Sheikh, R. S. Parhar, R. Bakheet, S. Saleh, K. Collison and F. Al-Mohanna1

Biological and Medical Research Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

1 Correspondence: Biological & Medical Research, MBC 03, King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. E-mail: futwan{at}kfshrc.edu.sa


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recruitment of leukocytes from bloodstream to extrahematic sites is tightly regulated by a variety of adhesion molecules that are expressed on the leukocytes and the vessel walls. In this manuscript, we describe the interactions between natural killer (NK) cells and activated, autologous platelets under physiologic flow. We found that surface-adherent human platelets are capable of recruiting human NK cells from flow and that this recruitment is characterized by an initial tethering followed by a rolling phase. Both phases were dependent on the adhesion molecule P-selectin and its counter-ligand on the NK cells (P-selectin glycoprotein ligand 1). Activation of rolling NK cells with inflammatory mediators commonly found in atherosclerotic plaques (interleukin-12 and leukotriene B4) causes immediate cessation of the rolling process and conversion to stationary adhesion. Blocking antibodies to the adhesion molecules membrane-activated complex-1 and leukocyte function antigen-1 inhibited this conversion. Our data suggest that platelets deposited at sites of vascular injury may provide an alternative substrate to endothelial cells for initial recruitment of NK cells to the vessel wall. This may result in extravasation of the NK cells if the appropriate chemotactic signal is applied. These data implicate the P-selectin and integrin family of adhesion molecules in the recruitment of NK cells to atherosclerotic sites.

Key Words: platelets • adhesion • ß2 integrins • shear stress


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Natural killer (NK) cells comprise approximately 10% of blood mononuclear cells. Although normally found mainly in the blood, in certain pathological situations, NK cells accumulate at extrahematic sites such as in atherosclerotic lesions [1 , 2 ], in the allograft infiltrate following rejection [3 ], and in the liver following virus infection [4 ]. NK cells mediate lysis of some virus-infected cells, transformed cells, and certain tumor cells without prior sensitization [5 ].

Leukocyte recruitment from blood vessels into extra-hematic sites is controlled by a series of adhesive interactions between the leukocyte and the vessel wall. NK cells/endothelial interactions have been reported to be dependent on P-selectin under static, nonflow conditions [6 , 7 ] and on P- or E-selectin of transfected Chinese hamster ovary cells under conditions of flow shear stress [8 ]. Several studies have reported that leukocyte function antigen-1 (LFA-1; CD11a/CD18) partially mediates the binding of NK cells to endothelium [9 , 10 ], and others have described the migration of NK cells across endothelial cell layers following chemotactic stimulus [11 ]. The adherence of NK cells to substrates other than endothelial cells has been less well studied. NK cells have, however, been shown to recognize ligands on extracellular matrix proteins, where the binding of NK cells to fibronectin via very late antigen (VLA)-4 and VLA-5 facilitates the migration of human NK cells [12 , 13 ].

At sites of vessel-wall damage, the primary event in the haemostatic reaction is deposition of platelets and fibrin [14 ]. Adhesive interactions between platelets and leukocytes contribute to several pathological conditions including atherosclerosis, thrombosis, and myocardial ischaemia, where significant tissue damage is thought to occur by release of degradative enzymes by immobilized leukocytes [15 16 17 ].

Although NK cells have been found at extrahematic sites such as atherosclerosis plaques [1 , 2 ], the mechanism(s) of their recruitment to these sites is yet to be delineated.

In this manuscript, we have used an in vitro flow-based vascular injury model to investigate the specific interactions between NK cells and autologous-activated platelets. We describe how surface-adherent platelets supply an alternative substrate for flowing NK cells that might be attracted to injured vessels and atherosclerotic sites. Analysis of the molecular mechanisms underlying NK cells/platelet interactions implicates the P-selectin in the initial tethering and rolling of NK cells and ß2 integrins in the strong adhesive interactions following NK cell activation under physiological flow shear stress.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Anti-P-selectin antibody (CD62P, clone 9E1, lot #APD05) and anti-P-selectin glycoprotein ligand 1 (PSGL-1) antibody (CD162, clone CMO-131, lot #EMF01) were purchased from R&D Systems (Minneapolis, MN). Anti-LFA-1 antibody (CD11a/CD18, clone MEM-83, AB 3981) and antimembrane-activated complex 1 (Mac-1) antibody (CD11b/CD18, AB 8879) were purchased from AbCam Ltd. (Cambridge, UK). Anti-CD42a antibody (cat. #348083) was purchased from Becton Dickinson (San Jose, CA). Anti-CD16 antibody (clone DJI30C) was obtained from Dako (Denmark), and anti-CD56 (lot #MO73880) was purchased from PharMingen (San Jose, CA). Recombinant interleukin (IL)-12 (RD1-212) was purchased from Research Diagnostics Inc. (Flanders, NJ). Thrombin was obtained from Organon Teknika Corp. (Durham, NC), and leukotriene B4 (LTB4; #70K3851) was obtained from Sigma Chemical Co. (St. Louis, MO). Magnetic cell sorter (MACS) cell isolation kits (#465-2) were obtained from Miltenyi Biotech (GmbH, Germany). Microslides, which are flat, glass, microcapillary tubes with a cross-section of 0.3 mm x 3.0 mm and a length of 50 mm, were purchased from Camlab Ltd. (Cambridge, UK).

Isolation of NK cells
Human venous blood was collected from healthy volunteers into buffered, preservative-free sodium heparin (10 U/ml). NK cells were isolated from peripheral blood mononuclear cells by depletion of human T cells, B cells, and myeloid cells. MACS cell isolation kits containing a cocktail of CD3, CD14, CD19, CD36, and anti-immunoglobulin (Ig)E antibodies were used according to the manufacturer’s instructions. NK cells were resuspended in 0.1% bovine serum albumin (BSA) in phosphate-buffered saline (PBS) containing 1 mM Ca2+ and 0.5 mM Mg2+ before the adhesion assay. NK cells of >95% purity, as judged by fluorescein-activated cell sorter analysis, were used for experiments. The isolated NK cells were heterogenous, containing CD16bright and CD56bright.

Isolation of platelets
Whole blood from the same NK cell donor was collected in citrate buffer and centrifuged at 290 g for 5 min, and the upper layer of platelet-rich plasma was harvested. The platelets were counted by coulter counter and diluted to 2 x 108cells/ml in PBS containing BSA (0.1%).

Preparation of platelet substrate
The microslides were placed in concentrated nitric acid overnight, cleaned thoroughly with running water for several hours, treated with aminopropyltriethoxysilane (Sigma Chemical Co., Dorset, UK), and dried completely in a 37°C incubator. The platelet suspension was loaded into the microslides by pipetting the suspension directly into them. The microslides were incubated for 30 min at room temperature to allow the platelets to settle, adhere, and spread onto the lower surface of the microslide. An essentially confluent monolayer of activated platelets was formed within the microslide.

In vitro flow-based adhesion assay
The in vitro flow-based adhesion assay system was similar to that described previously [18 19 20 ]. The microslide containing the monolayer of activated platelets was glued across the width of a microscope slide using super loctite glue. The microscope slide was placed on the light microscope stage. One end of the microslide was attached to a three-way electronic valve using silicon rubber tubing. This electronic valve allowed exchange between NK cell suspension or cell-free medium. The other end of the microslide was attached to a Harvard syringe pump (Harvard Apparatus, Holliston, MA). NK cell suspensions were drawn through the microslide for 3 min at a wall shear stress of 0.1 Pascal (Pa). The rate of flow (Q) of liquid through the microslide was controlled by the speed setting of the pump. The wall shear stress exerted on the platelet surface was calculated using the following equation: t = (6Q·{eta})/(w·h2), where {eta} is the viscosity of the suspending medium, h is the internal depth of the microslide, and w is the microslide internal width [20 ]. NK cell-platelet interactions were video-recorded (Hyper HAD CCD-IRIS/RGB, Sony, Riyadh, Saudi Arabia). Quantitation of adhesion and categorization of adhesion were determined by analysis of the video tapes using the OpenLab image processing system (Improvision, Coventry, UK). All experiments were conducted at room temperature.

To investigate the effects of activation, 1 ng/ml IL-12 in 0.1% BSA in PBS (1 mM Ca, 0.5 mM Mg) was superfused through the microslide after the NK cells had already adhered and established their rolling adhesion. Video recordings were used to quantify levels of adhesion at the required intervals, the percentage rolling, and the morphology of the adherent cells after activation. Shape change of NK cells after delivery of IL-12 was evident from video images.

Cell adhesion assay by flow cytometry
Freshly prepared platelets were washed in 10 mM EDTA in PBS and then incubated with 1 U/ml thrombin at 37°C for 20 min. The platelet suspension was washed once and fixed in 3.7% formaldehyde for 10 min at room temperature. The platelets were then marked by indirect immunostaining with monoclonal antibody (mAb) to the platelet marker CD42a followed by fluorescein isothiocyanate-labeled secondary antibody. Autologus NK cells were prepared, then marked by staining with phycoerythrin-labeled CD16/CD56. Platelets and NK cells were resuspended in PBS containing BSA (0.1%), Ca2+ (1 mM), and Mg2+(1 mM). Fixed, immunostained platelets were incubated with NK cells at a ratio of 20:1. Green and red fluorescence was measured on a FACScan flow cytometer (Becton Dickinson). Blocking experiments were performed by preincubating the platelets or NK cells with antibodies to P-selectin or its counter-ligand PSGL-1 and their respective isotype-matched control antibodies (30 min at room temperature).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
NK cell attachment to autologous platelet monolayer under flow is dependent on P-selectin
To determine whether naïve NK cells are able to form stable, adhesive bonds with autologous platelets under physiological flow, we studied the variation in the number of adherent NK cells over a period of time. At a wall shear stress of 0.1 Pa, NK cells bound efficiently to the platelet monolayer, 19 ± 2 cells/field. Approximately 97% of the adherent NK cells were rolling after initial contact with the platelet monolayer, and this level of rolling remained constant over a period of 10 min (P>0.05), with no obvious change in morphology.

Because the selectin family of adhesion molecules are intimately involved in the rolling adhesion observed after initial contact of NK cells with endothelial cells, we investigated the role of the adhesion molecule P-selectin in the initial recruitment of NK cells to the platelet surface. We found that when platelet monolayers were pretreated with P-selectin antibody (CD62P; 200 ng/ml), the level of NK cell adhesion was reduced by 91 ± 1% (mean±SEM; n=3). Blocking antibodies to the P-selectin counter-ligand PSGL-1 (CD162; 200 ng/ml) resulted in 92 ± 1% (mean±SEM; n=3) inhibition of binding of NK cells to platelets at flow shear stress of 0.1 Pa (Fig. 1 ). These characteristics are similar to the molecular mechanisms described previously for the adhesion of neutrophils to platelets under flow [18 , 21 , 22 ]. In contrast, blocking antibodies to LFA-1 (CD11a/CD18) had no significant effect (P>0.05; data not shown). P-selectin expression on the activated platelets was demonstrated using flow cytometry, which revealed that resting platelets bound minimally (GeoMean=38) to antibodies to P-selectin (Fig. 2 ); however, upon activation with thrombin (10 µg/ml), this binding increased significantly to approximately fourfold (GeoMean=121). Control experiments with isotype-matched IgG showed no effect. To confirm the role of P-selectin on platelet/NK cell interactions, we used flow cytometry to investigate the binding of autologous NK cells to activated platelets. In a series of experiments, we found that thrombin-activated platelets bound avidly to autologus NK cells (Fig. 3a and 3b ). This binding was significantly reduced in the presence of blocking antibodies to P-selectin on the platelet membrane or its counter-ligand PSGL-1 on the NK cell membrane. No effect was seen in the presence of similar concentrations of the isotype-matched control antibody.



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  		Figure 1. NK cell rolling on activated platelets. Inhibition of NK rolling on platelet-coated, glass microslides by blocking antibodies to P-selectin (200 ng/ml) or its counter-ligand PSGL-1 (200 ng/ml). Isotype-matched control antibodies (isotype, 200 ng/ml) had no effect. Percentage rolling was calculated as follows: [number of cells rolling/total number of cells in the field (rolling+adherent)] x 100.

 


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  		Figure 2. P-selectin expression on activated platelets. A flow cytograph of platelet labeled with anti-P-selectin antibody using indirect immunofluorescence showing fluorescence of thrombin-treated (10 µg/ml stimulated), platelets (blue), untreated (unstimulated) platelets (green), and isotype-matched IgG (red).

 


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  		Figure 3. NK cell/platelets binding is blocked by antibodies to P-selectin or its counter-ligand PSGL-1. Flow cytographs showing binding of NK cells to activated platelets using indirect immunofluorescence in double-label experiment. Platelets were labeled with anti-CD42a antibody and NK cells, labeled with anti-CD16 and anti-CD56 antibodies. The flow cytograph shows thrombin-activated platelets (i), in the presence of blocking antibody to P-selectin (ii), in the presence of blocking antibody to PSGL-1 (iii), and in the presence of isotype-matched IgG (iv). Unbound platelets were gated out by size. This is a representative experiment of three in which cells were isolated from three individual donors. (a) The result obtained using formaldehyde-fixed platelets and (b) the results obtained using freshly isolated platelets. These are representative experiments of at least four, and NK cells were obtained from four different donors.

 
Immobilization of rolling NK cells on rolling over platelets substrate by inflammatory mediators
IL-12 is one of the major inflammatory mediators found in extrahematic sites associated with atherosclerotic plaques [23 ]. This cytokine induces adhesion of NK cells to endothelial cells [24 ] and is known for its chemotactic activity toward NK cells. We therefore studied the sequence of adhesive events of the rolling NK cell following activation with IL-12. In a series of experiments, a bolus of NK cells was perfused across the platelet monolayer until rolling adhesion was established. IL-12 (1 ng/ml) was superfused over the rolling NK cells, and after a brief period of washout, morphological and quantitative changes were observed. Under such conditions, we found that the majority of rolling NK cells became stationary with time (Fig. 4a ). The rolling velocities changed from 24.06 ± 2.87 µm/s to 5.80 ± 2.03 µm/s in control and IL-12-treated NK cells, respectively. They remained stationary throughout the duration of the experiment. Another inflammatory mediator, the eicosanoid LTB4 (5 µM), which was also reported in the atherosclerotic plaque [25 ], caused a time-dependent cessation of rolling of NK cells over the platelet substratum (Fig. 4a) , with rolling velocities decreasing from 19.30 ± 3.50 µm/s in control to 5.70 ± 0.7 µm/s in LTB4-treated NK cells.



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  		Figure 4. NK cell rolling on activated platelets. (a) Rolling of NK cells on platelet-coated, glass microslides at a wall shear stress of 0.1 Pa in the absence ({diamondsuit}) and during superfusion of IL-12 (1 ng/ml, {blacksquare}) or LTB4 (5.5 µM, {blacktriangleup}). Data are the mean ± SEM for three experiments with cells isolated from three individual donors. (b and c) Reversal of the IL-12- and LTB4-induced inhibition of NK cell rolling on activated platelets by blocking antibody to the ß integrins, Mac-1 (100 ng/ml) and LFA-1 (100 ng/ml). Isotype-matched IgG had no effect. Each histogram represents the mean ± SEM, n = 3, with cells isolated from three individual donors.

 
Video observation revealed that stimulated cells (with IL-12 or LTB4) stopped rolling before changing shape from spherical to irregular. A proportion of the NK cells appeared phase-dark following shape change, which is consistent with appearance of transmigrating cells through vascular endothelium [26 ]. The cells did not recommence rolling over a period of 6 min and remained statically adherent to the substratum for the duration of stimulus perfusion.

NK cell immobilization by IL-12 and LTB4 is mediated by ß2 integrins
The NK cell receptor(s) mediating IL-12/LTB4-dependent immobilization was investigated. NK cells were allowed to establish rolling adhesions before superfusion of antibodies against NK cell ß2 integrins, LFA-1 (100 ng/ml) and Mac-1 (100 ng/ml), for 5 min at room temperature. An inflammatory mediator IL-12 (1 ng/ml) or LTB4 (5 µM) was perfused over the rolling NK cells, and subsequent immobilization was analyzed. We found that the decrease in the number of rolling cells after treatment with IL-12 or LTB4 was significantly inhibited by mAb to Mac-1 (CD11b; P<0.05, 100 ng/ml) or LFA-1 (CD11a; P<0.05, 100 ng/ml; Fig. 4b and 4c ). In contrast, isotype-matched, control IgG had no significant effect on this conversion.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
NK cells are a heterogeneous group of lymphocytes with prime functions in innate immunity. Resting NK cells exist mainly as two distinct subsets dictated by surface density of CD56 and CD16, namely CD56bright CD16dim and CD56dim CD16bright [27 , 28 ]. CD56bright CD16dim constitute 10% of resting NK cells and are immunoregulatory, whereas the majority (90%) are the cytolytic CD56dim CD16bright NK cells [28 29 30 ]. This proportion is maintained only in unstimulated NK cells, as CD56 antigen is up-regulated in stimulated CD56dim CD16bright [31 ].

Migration of NK cells to inflammatory sites requires their interaction with endothelial cells through an array of signaling molecules and a number of cytokine and chemokine receptors. Although the NK cell/endothelial interactions are relatively well documented, NK cells/platelet interactions are not well understood. Moreover, the adhesive response of NK cells and their role in induction of vessel wall injury following interaction with activated platelets are yet to be elucidated.

NK cells have been found in atherosclerotic lesions and plaques [1 , 2 , 32 ]; however, the mechanism(s) of their recruitment and extravasation to the lesions is not fully delineated.

In the present work, we attempt to address the early interactions of NK cells with vascular surfaces bearing adherent platelets on injured or denuded endothelium. We use an in vitro flow model to document the adhesive interactions of human NK cells with autologous, surface-adherent platelets contained in microslides under physiologic shear stress.

We show that unstimulated NK cells (total NK cells containing CD56dim CD16bright and CD56bright CD16bright) tether and roll freely on the platelet substratum. This rolling seems dependent on the platelet-borne P-selectin and its counter-ligand PSGL-1 on the NK cells. Evidence for this was drawn from the fact that blocking antibodies to these moieties inhibit tethering and rolling under physiologic flow, activated platelets exhibited increased expression of P-selectin, and binding of NK cells to thrombin-activated platelets is inhibited by these antibodies in flow cytometry experiments. These results are similar to those obtained with human neutrophils rolling on activated platelets or endothelial cell monolayers [33 34 ]. NK cells rolled continuously on the platelet surface for up to a period of 10 min with no obvious change in their morphology.

IL-12 is a heterodimeric cytokine produced by many cells such as B lymphocytes, monocytes, macrophages, neutrophils, and endothelial cells in response to a variety of soluble and particulate stimuli [35 ]. IL-12 has a wide range of functions including T helper cell type 1 cell development, regulation of cytokine synthesis, and lymphocyte proliferation [36 37 38 ]. The involvement of IL-12 in chronic vascular inflammation such as atherosclerosis has been demonstrated by a number of investigators [23 , 32 , 39 , 40 ]. The chemotactic activity of IL-12 toward NK cells has been demonstrated [41 ]; furthermore, activation of NK cells by IL-12 increases their binding to resting or IL-1-activated endothelial cells [41 ]. However, interactions of IL-12-activated NK cells with surface-adherent platelets have not been demonstrated. In this manuscript, we show that treatment of rolling NK cells on an autologous platelet monolayer with IL-12 causes immediate cessation of the rolling process with concomitant conversion to stationary attachment. This conversion was reversed by treatment of NK cells with blocking antibodies to LFA-1 or Mac-1 adhesion molecules. The question as to whether other inflammatory mediators, reported to be found in atherosclerotic plaques [25 ], cause similar cessation of rolling NK cells was addressed by using the eicosanoid lipid inflammatory mediator LTB4. We found that LTB4 caused similar cessation and induced firm adhesion of rolling NK cells to the microslide surface-adherent platelets. Furthermore, this effect was significantly inhibited in the presence of blocking antibodies to ß2 integrins LFA-1 or Mac-1.

Counter-ligands for ß2 integrins are many; depending on the cell type, these include intercellular adhesion molecule-1 (ICAM-1) [42 , 43 ], junctional adhesion molecule-1 (JAM-1) [44 45 46 47 ], and JAM-3 [48 ]. Whereas the ICAM family of adhesion molecules is a known endothelial counter-ligand for ß2 integrins [49 50 51 52 ], its involvement in platelet/NK cell interactions is not clear. However, the expression of a number of the JAM family of adhesion molecules including JAM-1 [44 45 46 ] and JAM-3 [48 ] on platelet membrane has been demonstrated. It is therefore tempting to speculate that JAM-1 and JAM-3 on platelets may act as counter-ligands for LFA-1 and Mac-1 expressed on NK cells following stimulation with IL-12 or LTB4.

The data presented in this paper suggest that similar to leukocyte/endothelial interactions, platelet P-selectin mediates tethering and rolling of NK cells through PSGL-1 counter-ligand and that proinflammatory stimuli found in chronic vascular inflammation, such as atherosclerosis lesions and plaques, cause cessation of this rolling, converting it to a firm adhesion through expression of the ß2 integrins LFA-1 and Mac-1 before NK cells commit to transplatelet migration.


   ACKNOWLEDGEMENTS
 
This work was supported by the Cardiovascular Research Program Funds and Research Centre Funds. The authors acknowledge Drs. A. Kwaasi and K. Khabar for their help and support and the many discussions regarding this manuscript. We also acknowledge the technical help of the flow cytometry core facility.

Received February 23, 2004; revised May 2, 2004; accepted May 3, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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