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(Journal of Leukocyte Biology. 2008;83:1069-1078.)
© 2008 by Society for Leukocyte Biology

Platelet–lymphocyte cross-talk

Nailin Li1

Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital (Solna), Stockholm, Sweden

1Correspondence: Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital (Solna), SE–171 76 Stockholm, Sweden. E-mail: nailin.li{at}ki.se


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ABSTRACT
 
Platelets and lymphocytes reciprocally regulate mutual functions, i.e., platelet–lymphocyte cross-talk. The heterotypic interactions have emerged as important regulatory mechanisms in the pathophysiological processes of thrombosis, inflammation, immunity, and atherosclerosis. Platelets influence lymphocyte function via direct cell–cell contact and/or soluble mediators. Hence, platelets enhance adhesion and cell migration of TH, T cytolytic (TC), NK, and B cells. Platelets affect other functional aspects of lymphocyte subpopulations in a complex manner. They may attenuate cytokine secretion and immunosuppressive responses of TH cells and enhance TC cell proliferation and cytotoxicity. Platelets promote isotype shifting and antibody production of B cells but ameliorate cytolytic activity of NK cells. On the other hand, lymphocytes can also regulate platelet aggregation and secretion, as well as the effector cell function of platelets in immune defense. The two cell types collaborate in transcellular phospholipid metabolism, CD40–CD40 ligand-mediated intercellular signaling, and their involvements in atherogenesis. The research perspectives of platelet–lymphocyte cross-talk have also been addressed.

Key Words: thrombosis • inflammation • atherosclerosis


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INTRODUCTION
 
Thrombosis and inflammation are closely linked pathophysiological processes [1 ]. The principal cellular components of thrombosis and inflammation, platelets, and leukocytes, respectively, are known to regulate reciprocal functions, i.e., platelet–leukocyte cross-talk, and participated in both pathophysiological processes [2 , 3 ].

Much of our knowledge of platelet–leukocyte cross-talk is accumulated during the last two decades, albeit the interaction was first observed more than 100 years ago by Giulius Bizzozero [4 , 5 ]. Platelet interactions with granulocytes and monocytes have been studied extensively and have been reviewed previously [6 7 8 ]. Recently, increasing evidence suggests that important interactions also exist between platelets and lymphocytes and that this heterotypic cross-talk plays pivotal roles in thrombosis, inflammation, and atherogenesis. The present review will thus cover the recent advances of platelet–lymphocyte cross-talk and will also elucidate its impact in atherosclerosis, a disease tightly linked to thrombosis and inflammation [1 , 9 , 10 ].


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INFLUENCE OF PLATELETS ON LYMPHOCYTE ADHESION AND HOMING
 
Continuous migration of lymphocytes, between the circulating blood and the lymphatics, from one peripheral lymphoid tissue to another and from the bloodstream to inflammatory sites, is a crucial feature of lymphocyte function and immune responses. Similar to other leukocytes, lymphocyte migration follows the cascade of selectin-mediated tethering and rolling, integrin-supported firm adhesion, and subsequent transendothelial migration. The migration cascade of all lymphocyte subsets of TH (CD3+/CD4+) cells, T cytolytic (TC; CD3+/CD8+) cells, B cells, and NK cells is modulated by platelets (Fig. 1 ). Lymphocytes can roll on and subsequently adhere to immobilized, activated platelets under flow conditions, mainly via platelet P-selectin and lymphocyte P-selectin glycoprotein ligand-1 (PSGL-1) and sialyl saccharides [11 12 13 ]. The cross-linking of P-selectin with PSGL-1 induces clustering of {alpha}L integrin and subsequently, enhances lymphocyte adhesion via ICAM-1 binding [14 ]. This suggests that transformation of selectin-mediated lymphocyte rolling to integrin-mediated firm adhesion is a physiological consequence of P-selectin ligation. Moreover, T cells have greater adhesiveness than B cells [11 ], and the {gamma}/{delta} T cell subset has higher binding affinity to P-selectin than the {alpha}/β T cell subset [12 ]. The latter indicates that T cells, especially {gamma}/{delta} T cells, may be selectively recruited at inflammatory sites where P-selectin expression is up-regulated. Platelets also enhance TH cell adhesion on subendothelial matrix under flow conditions by forming platelet–TH cell conjugates and via ligations of P-selectin, CD40 ligand (CD40L), as well as {alpha}IIbβ3 and β1 integrins [15 ]. Platelet-derived microparticles readily bind to leukocytes, endothelial cells, and subendothelial matrix and subsequently, enhance adhesion of monocytes and granulocytes [16 17 18 ]. The similar enhancement is likely true for lymphocytes, albeit direct evidence remains to be obtained.


Figure 1
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  		Figure 1. Influences of platelets on the activities of different lymphocyte subpopulations.

Using various animal models, it has been shown that activated platelets tethered on high endothelial venules of the peripheral lymph nodes can capture passing lymphocytes [19 ], and that activated platelets bind to circulating lymphocytes and support lymphocyte homing at the high endothelial venules [20 ]. Platelet-mediated lymphocyte recruitment involves a "sandwich" ligation via lymphocyte PSGL-1–platelet P-selectin–endothelial cell-expressed peripheral node addressin (PNAd). The latter is a ligand for P-selectin and L-selectin [19 , 21 ], and P-selectin–PNAd ligation may fully support lymphocyte delivery in L-selectin-deficient mice, as infusion of activated platelets reconstitutes T lymphocyte homing in L-selectin knockout (KO) mice [20 , 22 ]. Thus, platelet-mediated lymphocyte delivery is particularly meaningful for memory lymphocytes that lack L-selectin expression. Furthermore, platelet P-selectin and platelet–lymphocyte conjugation enhances pulmonary lymphocyte recruitment in a murine model of allergic inflammation [23 ]. Platelets can also facilitate TH cell recruitment in postischemic sinusoids in a warm hepatic ischemia/reperfusion mouse model and subsequently, aggravate microvascular/hepatocellular injury [24 ]. It should, however, be noted that most of the above data were obtained at the venous levels of shear stress. It remains undefined if and how platelets assist lymphocyte adhesion under arterial shear stress in vivo.


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EFFECTS OF PLATELETS ON T CELL ACTIVATION
 
In addition to facilitating T cell adhesion, platelets may influence other functional aspects of T cells (Fig. 1) . Platelet-released platelet factor 4 (PF4) regulates multiple T cell activities via binding to glycosaminoglycan [25 ] and the chemokine receptor CXCR3B [26 ] on the T cell surface [27 , 28 ]. PF4 inhibits monocyte-dependent and CD3/CD28 antibody ligation-induced T cell proliferation and cytokine release [25 ], as well as mitogen-induced suppressor cell generation of T cells [28 , 29 ]. Interestingly, it was recently found that PF4 modulates regulatory T (TREG; CD4+CD25+) cells and non-TREG (CD4+CD25–) cells in an opposite manner [30 ]. Thus, PF4 inhibits CD4+CD25– T cell proliferation but stimulates proliferation of CD4+CD25+ TREG cells; the latter cells, however, lost their ability to inhibit CD4+CD25– T cell proliferation [30 ]. These findings indicate that PF4 plays a complex role in the regulation of T cell responses and that further work in an in vivo setting is warranted to elucidate physiological consequences of this phenomenon.

Besides PF4, other platelet-released mediators may also modulate T cell function. Allergen binding to IgE-coated platelets leads to serotonin release and subsequently, initiates T cell-dependent contact sensitivity [31 ]. Platelet-released serotonin may also supplement mast cells and maintain normal contact sensitivity of T cells in mast cell-deficient mice [32 ]. Calpain, a platelet-released, Ca2+-dependent neutral protease, can cleave T cell-expressed CD43 and contributes to the pathogenesis of the Wiskott-Aldrich synthrome (an inherited disease involving defects of platelets and T lymphocytes) [33 ]. Moreover, an unidentified protein released by high shear-activated platelets may induce significant proliferation of naive T lymphocytes through a dendritic cell activation-dependent mechanism [34 ].

Platelets seem to mostly enhance the function of TC cells. Platelets augment adenovirus infection-evoked IFN-{gamma} production and cytolytic capacity of TC cells [35 ] via signaling mechanisms mediated by platelet-expressed CD40L (CD154). This is evidenced by the fact that injection of activated platelets from normal but not CD40L-deficient mice enhanced the generation of IFN-{gamma}-producing TC cells and the total cytolytic activity of TC cells [35 ]. The importance of platelets for TC cell function is also suggested by a recent study showing that platelet depletion reduces intrahepatic accumulation of virus-specific TC cells and organ damage in a mouse model of acute viral hepatitis [36 ]. Transfusion of normal but not activation-blocked platelets in platelet-depleted mice restored accumulation of cytotoxic T lymphocytes and severity of disease [36 ].

It should be stressed that platelets exert their influence on T cell subsets individually and through multiple mechanisms and mediators. The same platelet factor may affect different T cell subset differently, and different platelet mediators may influence the same T cell subset differently. The true outcome of platelet–T cell cross-talk will thus depend on the physiological or pathophysiological microenvironment, as well as the negotiation of multiple mechanisms.


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IMPACTS OF PLATELETS ON B CELL FUNCTION
 
Platelets also modulate humoral immunity. Platelets can directly stimulate proliferation and antibody production of B cells in vitro via CD40L-mediated cell–cell contact [37 ]. In vivo evidence shows that platelets sufficiently support B cell isotype switching and that platelet depletion prior to adenovirus infection decreases the efficiency in the production of adenovirus-specific IgG but not IgM [35 ]. In collaboration with TH cells, platelets can also enhance germinal center formation [38 ]. CD40–CD40L ligation seems to be crucial for this platelet–B cell cross-talk, as CD40L-deficiencent mice failed to elicit B cell isotype switching, and infusion of CD40L-expressing platelets can restore the isotype shifting [35 ]. It has also been shown that infusion of wild-type platelet-derived microparticles into the CD40L-deficient mice can deliver the CD40L stimulus that results in germinal center formation [39 ]. Interestingly, platelets can exert CD40L signaling, not only locally by direct cell–cell contact but also remotely by releasing soluble CD40L, as infusion of the platelet-free supernatant from activated platelets induced isotype switching [35 ]. Taken together, platelet–B cell cross-talk is of great importance, at least for the following two reasons. First, platelet CD40L-mediated signaling supports the maturing of the antibody response prior to expansion of the TH cell compartment, which traditionally provides the CD40L signal. Therefore, platelet CD40L-mediated signaling is critical for the prompt response of humoral immunity. Second, antigen-specific T cells are rare under physiological conditions; platelets can thus strengthen the signals required for robust, adaptive, humoral immunity.


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PLATELET INTERACTION WITH NK CELLS
 
Malignancy is associated with an increased thrombotic risk [40 ]. Certain tumor cells can induce platelet activation [40 41 42 ]. The capacity of tumor cells to induce platelet aggregation is positively correlated with the metastatic potential of the tumor [43 ], and the blockade of platelet adhesion/aggregation may attenuate tumor growth, migration, and metastasis [44 , 45 ]. It has previously been shown that tumor cell-conjugated platelets impede tumor cell lysis by NK cells, likely via surface shielding of the platelet cloak, and that platelet depletion can reduce the tumor seeding of NK cell-sensitive tumor cells in the target organs [46 ]. A recent study using a mouse model of activation-defective platelets elucidated further that platelets enhance tumor metastatic potential by hampering NK cell-mediated elimination of tumor cells [47 ]. Hence, deficiency of platelet activation markedly reduced the survival of embolic tumors in the lungs, and NK cell depletion restored the reduction [47 ].

However, platelets do not only hinder NK cell activity; activated platelets adhere to NK cells with high affinity to form heterotypic conjugates, and the conjugation is independent from NK cell activation [48 ]. Immobilized platelets support NK cell tethering and rolling via P-selectin–PSGL-1 ligation, and the rolling NK cells are readily converted to β2 integrin-dependent firm adhesion in the presence of IL-12 and leukotriene B4 (LTB4) [13 ]. Thus, adhered platelets may facilitate NK cell infiltration into their sites of action.


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INFLUENCES OF LYMPHOCYTES ON PLATELET ACTIVATION
 
Platelets modulate lymphocyte activation and vice versa. Apart from being the principal cellular element in thrombosis and hemostasis, platelets can function as effector cells in the immune defense [49 ]. Platelets express IgE receptors with a high density [50 , 51 ], and IgE-dependent effector function of platelets is an important defense mechanism in parasitic infection [52 ]. IgE binding induces platelet release of cytotoxic mediators that subsequently kill the parasites, such as schistosomiasis and filariasis [52 , 53 ]. Interestingly, this effector function of platelets is differentially regulated by lymphokines released from different T cells [54 ]. TH cell-released IFN-{gamma}, TNF-{alpha}, and TNF-β can induce and/or enhance platelet cytotoxicity [55 , 56 ], and TC cell-released platelet activity suppressive lymphokine (ubiquitin) may inhibit IgE-dependent platelet cytotoxicity [57 , 58 ]. Platelets express IgG receptors too [59 ], and the IgG immune complex can induce platelet aggregation and serotonin secretion [60 ].

Lymphocyte-released cytokines also regulate other platelet functions. IFN-{gamma} can enhance platelet dense granule secretion and platelet conjugation with leukocytes [61 ], and IL-2 may attenuate platelet aggregation but enhance platelet {alpha}-granule secretion and arachidonic metabolism via a mononuclear cell-dependent mechanism [62 ]. Furthermore, ecto-ATPase of lymphocytes may convert ATP released from platelets and/or other blood cells to ADP, which subsequently enhances platelet aggregation [63 ]. Hence, lymphocytes have multiple influences on platelet function and may exert a stimulatory or inhibitory effect on platelets upon different physiological and pathophysiological stimuli.


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HETEROTYPIC CONJUGATION/AGGREGATION OF PLATELETS AND LYMPHOCYTES
 
Platelets and leukocytes may conjugate under flow conditions [4 ]. Granulocytes, lymphocytes, and monocytes can all form heterotypic conjugates [64 65 66 ]. However, the propensity to form heterotypic conjugates/aggregates differs between leukocyte subpopulations, with monocytes showing the greatest and lymphocytes the least propensity [64 , 66 ]. We [48] have recently investigated heterotypic conjugation among different lymphocyte subpopulations. We found that platelet–lymphocyte conjugates constitute ~3% of circulating lymphocytes, and platelet conjugation is most common among large (monocyte-sized) lymphocytes [48 ]. Using cell-type or subpopulation-specific stimuli, it was evident that platelet activation slightly increased platelet–T cell conjugation, mainly to TC cells (from 3% to 7%), but markedly elevates platelet–NK cell conjugation (from 3% to 12%). T cell activation increased heterotypic conjugation in TH (up to 12%) and TC cells (15%), and NK cell activation affected platelet–NK cell aggregation little. Neither platelet activation nor B cell activation enhanced platelet–B cell conjugation [48 ]. Activation-dependent, heterotypic conjugation was mainly found among large cells, with increased percentages of conjugated cells and more platelets bound per lymphocyte [48 ]. For example, T cell activation may increase heterotypic conjugation among large T cells to ~20%, and platelet activation elevates platelet-conjugated, large NK cells to ~30%. Platelet-binding capacity of lymphocytes is, however, much lower than that of monocytes and granulocytes, most of which form heterotypic conjugates upon intensive platelet activation [66 ]. On the other hand, lymphocytes have a much longer life span and circulating time than monocytes and granulocytes and may shuttle between the circulating blood and the lymphatics. Hence, it is desirable to clarify which lymphocyte subsets have higher tendency for heterotypic conjugation and how platelet conjugation influences lymphocyte migration. The platelet-conjugating propensity is proportional to the P-selectin-binding capacity of lymphocyte subsets, in which TH, TC, and NK cells have much higher P-selectin-binding capacity than that of B cells [67 ]. Interestingly, P-selectin-binding potency in T memory cells is more than twofold higher than that of naïve T cells [67 ]. This suggests that high P-selectin-binding potency of T memory cells may compensate their loss of surface L-selectin. Thus, favorable platelet/P-selectin binding of large/activated and memory lymphocytes may selectively enhance their infiltration at inflammatory and immune response sites.

Multiple ligand-receptor ligations are involved in platelet–leukocyte aggregation, i.e., P-selectin (CD62P) binding to its ligands PSGL-1 [68 69 70 ] and CD15 [71 ], GPIb–CD11b ligation [72 ], fibrinogen bridging of platelet GPIIb/IIIa and leukocyte CD11/CD18 [70 , 73 ], as well as bridging of CD36 antigens (present on both cell types) by thrombospondin [74 ]. Similar to these earlier findings, we showed that platelet–lymphocyte conjugation initiated by platelet activation was abolished by P-selectin blockade and reduced by inhibition of GPIIb/IIIa, CD11b, or CD40L. Platelet–lymphocyte conjugation initiated by lymphocyte activation was partially inhibited by blocking each of the above adhesion molecules but was more markedly inhibited by the cocktailed blockade [48 ]. Therefore, it appears that P-selectin ligation is essential, and GPIIb/IIIa, CD40L, and CD11b also contribute to the heterotypic conjugation.


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CD40–CD40L LIGATION IN PLATELET–LYMPHOCYTE CROSS-TALK
 
CD40 and its ligand CD40L are members of the TNFR and TNF superfamily [75 ], and their interaction has received much attention in recent years [76 77 78 ]. CD40 is institutively expressed on mature B cells, platelets, some TH and TC cells, as well as a number of other cell types [75 , 79 , 80 ], and CD40L is predominantly expressed on platelets and TH cells upon activation [81 ]. CD40–CD40L interaction is a bridge between humoral and cellular arms of the immune responses. This interaction was originally thought to be restricted to T and B cells, namely TH cell-driven activation, proliferation, differentiation, and isotype shifting of B cells, germinal center formation, as well as activation and clonal expansion of TH and TC cells [82 83 84 ]. Accumulating evidence indicates that CD40–CD40L interaction is also involved in many other inflammatory processes, including platelet–lymphocyte cross-talk. CD40L-expressing T cells may induce platelet P-selectin expression and release of the chemokine RANTES via MAPK p38 signaling [85 ]. Direct cell–cell contact via T cell CD40L and platelet CD40 seems to be critical and sufficient for the cross-talk, as fixed CD40L-expressing T cells were just as effective as live cells, and CD40-blocking antibodies abrogated the enhancement [85 ]. The engagement of recombinant soluble CD40L with platelet CD40 can also induce the similar platelet responses [80 ]. Furthermore, CD40–CD40L ligation enhances β3 integrin activation [80 ], and CD40L can directly bind platelet β3 integrin under high shear stress [77 ], both of which can stabilize arterial thrombi.

Interestingly, platelet-released RANTES may, in turn, enhance T cell adhesion on an endothelial cell monolayer [85 ]. As already mentioned above, CD40L-expressing platelets may enhance TC cell activity, such as enhancement of IFN-{gamma} production and cytolytic capacity of TC cells [35 ]. Infusion of CD40L-expressing platelets may restore antigen-induced isotype shifting of B cells that is absent in CD40L-deficient mice [35 ]. Recombinant CD40L also increases proliferation and cytokine production of TH and TC cells [83 ]. Therefore, CD40–CD40L interaction has emerged as an important regulatory mechanism in homo- and heterotypic cell–cell interactions among platelets, T cells, and B cells. Clinical evidence shows that elevated CD40L release and/or surface expression of platelets and T cells are associated with acute coronary syndromes [86 ] and suggests that CD40L–CD40 interaction may play a pivotal role in the long-term atherosclerotic process and the triggering and propagation of acute coronary syndromes.


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TRANSCELLULAR METABOLISM BETWEEN PLATELETS AND LYMPHOCYTES
 
Phospholipid metabolism is an important aspect of platelet and leukocyte activation. Upon cellular activation, membrane phospholipids are cleaved by phospholipase A2 (PLA2) to release arachidonic acid (AA) and lyso-glyceryl-phosphocholine, which are further metabolized in platelets and leukocytes by various enzymes. Among the diverse metabolites, platelets convert AA to thromboxane A2 (TXA2) and to a much less extent, to prostacyclin/PGI2 following the actions of cyclooxygenase, TX synthase, and prostacyclin synthase. Leukocytes oxygenate AA into 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) via 5-lipoxygenase (5-LO). Thereafter, a dehydrase catalyzes the conversion of 5-HPETE to LTA4, which is subsequently converted to LTB4 and LTC4 by a hydrolase and a GST, respectively [87 ]. The other product of PLA2, lyso-glyceryl-phosphocholine, is converted into a platelet-activating factor (PAF) by a specific acetyltransferase in platelets and leukocytes [88 , 89 ].

As the complex phospholipid metabolism is carried out in individual activated platelets and leukocytes, platelets and leukocytes as well as other cells (e.g., endothelial and red cells) may collaborate in their phospholipid metabolism, i.e., transcellular metabolism [90 , 91 ]. Lymphocytes can take up AA and incorporate it into the membrane phospholipids, but they have minimal capacity to convert AA into metabolites [92 ]. Platelets, on the other hand, can synthesize and release a large quantity of the PG endoperoxide PGH2 and can efficiently convert the latter into TXA2 but not PGI2 [91 ]. When activated platelets and lymphocytes were cocultured, lymphocytes can uptake platelet-released PGH2 and convert it into PGI2 [93 ], which may in turn, attenuate activation of platelets and perhaps also lymphocytes themselves. Similarly, platelets are capable of using lymphocyte-released AA to enhance TX synthesis [94 ] that may subsequently amplify platelet activation. Evidence from a study of a platelet–granulocyte interaction suggests that the transcellular metabolism is enhanced by close cell–cell contact, as P-selectin blockade prevented the heterotypic conjugation and subsequently reduced transcellular metabolism of TXB2 and LTC4 [95 ].

Transcellular metabolism can also lead to the new products, i.e., lipoxin (LX)A4 and B4, which neither platelets nor leukocytes can produce alone [96 ]. Thus, platelets use the leukocyte-derived, 5-LO-catalyzed product LTA4 to synthesize LXs by means of 12-LO, and leukocytes may use the platelet-derived, 12-LO-catalyzed product 12-hydroxyeicosatetraenoic (12-HETE) to produce LXs via 5-LO action [97 ]. These LXs or their analogs have been shown to modulate lymphocyte function [98 ], such as attenuating cytotoxic activity of NK cells [99 ], TNF-{alpha} production of T cells [100 ], as well as lymphocyte infiltration during allergic airway responses [101 ].

Another important phenomenon of transcellular biosynthesis involving platelets and leukocytes is PAF generation. Activated platelets and leukocytes produce PAF, but coincubation of activated platelets and neutrophils can increase PAF generation by greater than or equal to twofold, as compared with that produced by the two cell types separately. This transcellular biosynthesis of PAF requires the activation of both cell types but not cell–cell contact and seems to depend on platelet-derived lyso-PAF [102 ]. Although direct evidence of a transcellular PAF synthesis between platelets and lymphocytes has yet to be documented, such an intercellular cooperation is likely, as lymphocytes do produce PAF [103 ]. Taken together, phospholipid transcellular metabolism is complex and is an important regulatory mechanism of platelet and lymphocyte function.


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PLATELETS, LYMPHOCYTES, AND THEIR CROSS-TALK IN ATHEROGENESIS
 
Atherosclerosis is an inflammatory and thrombotic disease, and platelets and lymphocytes are involved in the whole pathogenetic process of atherosclerosis (Fig. 2 ) [9 , 10 , 49 , 104 ].


Figure 2
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  		Figure 2. Platelet–lymphocyte cross-talk in atherosclerosis. plt-lym agg., Platelet–lymphocyte aggregate; B, B cells; PDMPs, platelet-derived microparticles; M{phi}, macrophage; ECs endothelial cells; SMC, smooth muscle cell.

Platelets patrol in and survey the integrity of the cardiovascular system. They precisely discriminate between normal and abnormal endothelial lining and between the integral and disrupted vessel wall and readily roll and subsequently adhere on activated endothelial cells and the injured vessel wall. Adhered platelets restore the vessel integrity and help to achieve hemostasis, but they may also propagate platelet activation to initiate thrombus formation. Accumulating evidence indicates that platelet adhesion and/or thrombus formation on the arterial surface initiate atherosclerotic lesion formation [104 , 105 ]. Prolonged blockade of platelet adhesion by inhibiting GPVI [105 ] or GPIIb [106 ] profoundly attenuated arteriosclerotic lesion formation in apolipoprotein E (ApoE) KO mice. Using a P-selectin–KO mouse model, platelet P-selectin was also shown to be important for the development of an atherosclerotic lesion [107 ]. Infusion of activated platelets leads to platelet–leukocyte conjugation and enhances the adhesion of platelets and platelet–leukocyte conjugates on atherosclerotic lesion. The platelets can then transfer or deposit platelet-derived chemokines, such as RANTES and PF4, to leukocytes, endothelium, and the lesion and subsequently, exacerbate atherogenesis [49 , 108 109 110 ].

Platelets display elevated adhesiveness on atherosclerotic lesions [106 ]. Indeed, platelets are present in atherosclerotic plaques but not in the normal arterial wall [110 ], as evidenced by the presence of platelet-specific antigen CD41 and the platelet-released chemokines PF4 and RANTES in human atherosclerotic lesions but not in normal vasculature [108 , 110 ]. Platelets in atherosclerotic plaques are found as free cells and/or phagocytosed cells in foam cells and macrophages [111 ]. They are usually observed as individual cells in the intima and/or as platelet aggregates in the area of plaque rapture and erosion [81 ]. Clinical evidence continues to emerge and indicates the importance of platelets in thrombotic and inflammatory processes of lesion development. Recently, a high plasma level of the platelet-derived chemokine neutrophil-activating peptide-2, which may destabilize atherosclerotic plaques, was found in acute coronary syndromes, suggesting a role of platelets in vascular inflammation [112 ]. All of these findings support that platelets are a major player in initiation and development of the atherosclerosis.

Since the first detection of lymphocytes in a human atherosclerotic plaque some 20 years ago [113 , 114 ], a large body of evidence indicates the importance of lymphocyte infiltration for atherosclerotic lesion development [9 , 10 ]. T cells can already be found in fatty streaks and increase to 10–20% of the lesional cell component in advanced human atherosclerotic lesions [113 , 115 ]. They are mostly activated T cells bearing TCR-{alpha}β and are predominantly type 1 TH cells [114 , 116 ]. The latter secretes IFN-{gamma}, IL-2, TNF-{alpha}, and TNF-β [115 ], which may cause activation of other lesional cells, promote vascular inflammation, and thus, augment lesion development. The concept is supported by animal studies showing that transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient ApoE KO mice [117 ], and CD4+ cell deficiency attenuates atherosclerotic lesion development in the animal model [118 ]. Similarly, disruption of the signaling pathway of TH cell activation, deficiency or blockade of TH cell-derived proinflammatory cytokines reduces atherogenesis in ApoE KO mice [10 , 119 120 121 122 123 124 ]. In addition to type 1 TH cells, atherosclerotic lesions contain moderate numbers of type 2 TH cells, TC cells, NK T cells, as well as occasional B cells [115 , 125 ]. Despite the moderate numbers of these cell types, they may still wield important influences on atherogenesis [115 ]. For instance, B cells may display a remarkable atheroprotective effect, as transfer of B cells from atherosclerotic ApoE KO mice significantly reduced atherosclerotic lesion development in young ApoE KO mice [126 ]. Therefore, different lymphocytes act in concert to regulate atherosclerotic plaque formation.

Platelets and lymphocytes each play major roles in atherogenesis. There is also evidence showing that platelets and lymphocytes modulate mutual involvement in atherogenesis via complex mechanisms (Fig. 2) . As already mentioned above, immobilized platelets and lymphocyte-conjugated platelets enhance lymphocyte adhesion on the vessel wall [19 , 20 , 22 ], and platelets are critical for the infiltration of lymphocytes into the inflammatory sites [23 ]. Platelets and platelet-derived microparticles can exacerbate atherosclerotic lesion formation [105 , 108 , 127 , 128 ] and seem to enhance lymphocyte and monocyte accumulation in the arterial intima [105 ]. Activated platelets release various growth factors (such as platelet-derived growth factor and TGF-β), chemokines (PAF, PF4, and RANTES), and cytokines (IL-1β and CD40L) [104 , 108 , 110 ], which display multiple influences on lesion formation. For instance, RANTES enhances T cell infiltration [85 ] and is pro-atherosclerostic [108 , 127 ]. In contrast, PF4 inhibits T cell proliferation and cytokine release [25 ] and may be of anti-atherosclerotic. Moreover, platelets may promote isotype-shifting and antibody production of B cells [35 ], which have emerged as a protective force in atherosclerosis [129 ]. Nevertheless, it remains to be elucidated how platelets influence T cell proliferation and cytokine production in the plaque and if platelets indeed facilitate B cell antibody production in the plaque. It should also be noted that deposition of platelet-released mediators in the atherosclerotic lesion seems to be important for platelet regulation of other lesional cells. This is because platelets are not the major source of microparticles isolated from the homogenates of human atherosclerotic plaques [130 ]. Thus, platelets, lymphocytes, as well as other lesional cells reciprocally regulate their involvements in atherogenesis.


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RESEARCH PERSPECTIVE OF PLATELET–LYMPHOCYTE CROSS-TALK
 
There is not doubt that platelet–lymphocyte cross-talk plays important roles in inflammation, immune responses, thrombosis, and atherosclerosis. Much of the elaborate cross-talk between the two cell types is, however, far from clear. With regard to platelet-mediated lymphocyte adhesion on the vessel wall, a major part of the information is obtained under venous flow conditions. Little is known if and how platelets support lymphocyte adhesion under arterial flow conditions, which is more relevant to lymphocyte infiltration in the atherosclerotic lesion. As lesional lymphocytes are mainly TH cells, do platelets selectively support the adhesion and migration of this lymphocyte subpopulation? There is plenty of room for a better understanding of the inter-/intracellular signaling mechanisms of platelet–lymphocyte cross-talk, such as the intracellular signaling pathway behind platelet priming by cytokines. Moreover, the information about platelet–lymphocyte interaction in vivo is largely generated from various animal models, which do not necessarily reflect the reality of humans. Angioplastic interventions expose a subendothelial and/or atherosclerotic lesion matrix that induces instant platelet adhesion and aggregation. It is desirable to investigate if and how adhered platelets enhance lymphocyte and monocyte migration into the intervention sites and if the platelets may influence the atheroprotective or pro-atherosclerotic activities of infiltrated lymphocytes. Thus, platelet–leukocyte cross-talk of humans in different pathophysiological settings needs to be elucidated further. It is predictable that more and more new, interesting findings will continue to emerge in the field of platelet–lymphocyte cross-talk. Better understanding of the interaction will be helpful for our campaigns against the atherothrombotic diseases.


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ACKNOWLEDGEMENTS
 
The author’s work is supported by the Swedish Heart-Lung Foundation, the Swedish Research Council, the Swedish Medical Association, the Karolinska Institute, the Swedish Diabetes Research Foundation, and the Stockholm County Council. The author is indebted to his collaborators in the research of platelet–leukocyte cross-talk.

Received September 10, 2007; revised December 17, 2007; accepted December 17, 2007.


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