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Thematic review series: The Immune System and Atherogenesis. The unusual suspects:an overview ofthe minor leukocyte populations in atherosclerosis

Open AccessPublished:March 16, 2005DOI:https://doi.org/10.1194/jlr.R500003-JLR200
      Atherosclerosis is a complexinflammatory disease process involving an array of cell types and interactions. Although macrophage foam cells and vascular smooth muscle cells constitute thebulk of the atherosclerotic lesion, other cell types have been implicated in thisdisease process as well. These cellular components of both innate and adaptiveimmunity are involved in modulating the response of macrophage foam cells andvascular smooth muscle cells to the retained and modified lipids in the vesselwall as well as in driving the chronic vascular inflammation that characterizesthis disease.
      In this review, the involvement of a number of less prominentleukocyte populations in the pathogenesis of atherosclerosis is discussed. Morespecifically, the roles of natural killer cells, mast cells, neutrophils,dendritic cells, γδ T-cells, natural killer T-cells, regulatory T-cells,and B-cells are addressed.
      Atherosclerosis is a complexand chronic inflammatory disease process affecting large and medium-sizedarteries. This disease is characterized by the retention and modification oflipids in the vascular wall followed by the infiltration of inflammatory cells(
      • Glass C.K.
      • Witztum J.L.
      Atherosclerosis: the road ahead.
      ). The macrophage foam cell isthe predominant inflammatory cell present in the atherosclerotic plaque and isessential for the development of atherosclerosis (
      • Smith J.D.
      • Trogan E.
      • Ginsberg M.
      • Grigaux C.
      • Tian J.
      • Miyata M.M.
      Decreased atherosclerosis in micedeficient in both macrophage colony-stimulating factor (op) andapolipoprotein E.
      ,
      • Gosling J.
      • Slaymaker S.
      • Gu L.
      • Tseng S.
      • Zlot C.H.
      • Young S.G.
      • Rollins B.J.
      • Charo I.F.F.
      MCP-1deficiency reduces susceptibility to atherosclerosis in mice that overexpresshuman apolipoprotein B.
      ). Asthe lesion progresses, the migration of fibroproliferative vascular smooth musclecells derived from either the underlying medial layer or circulating progenitorcells contributes to the formation of the stabilizing fibrous cap. Overlying theplaque is a layer of endothelial cells, influenced by the local hemodynamicprofile and responsible for homing inflammatory cells to this site of retainedand modified lipids (
      • VanderLaan P.A.
      • Reardon C.A.
      • Getz G.S.
      Site specificity of atherosclerosis: site-selective responsesto atherosclerotic modulators.
      ). Finally,T- and B-lymphocytes have been implicated in atherogenesis, primarily throughcytokine secretion and immunoglobulin production, respectively. During the past10 years, it has been increasingly recognized that although they are not requiredfor atherogenesis, T- and B-cells are able to modulate the progression of thisdisease despite their relatively low numbers in the plaque (
      • Zhou X.
      • Nicoletti A.
      • Elhage R.
      • K.Hansson G.
      Transfer of CD4+ T cells aggravatesatherosclerosis in immunodeficient apolipoprotein E knockout mice.
      ,
      • Reardon C.A.
      • Blachowicz L.
      • White T.
      • Cabana V.
      • Wang Y.
      • Lukens J.
      • Bluestone J.
      • Getz G.S.S.
      Effect of immune deficiency on lipoproteins and atherosclerosis in maleapoprotein E deficient mice.
      ,
      • Dansky H.M.
      • Charlton S.A.
      • Harper M.M.
      • Smith J.D.
      T and B lymphocytes play a minor role inatherosclerotic plaque formation in the apolipoprotein E-deficient mouse.
      ,
      • Song L.
      • Leung C.
      • Schindler C.
      Lymphocytes are important in early atherosclerosis.
      ,
      • Major A.S.
      • Fazio F.
      • Linton M.F.
      B-lymphocyte deficiency increases atherosclerosis inLDL-receptor-null mice.
      ,
      • Caligiuri G.
      • Nicoletti A.
      • Poirier B.
      • Hansson G.K.
      Protective immunity against atherosclerosiscarried by B cells of hypercholesterolemic mice.
      ). Numerous studies have demonstrated that T-cells inparticular have the capacity to modulate the development of atherosclerosis, andtheir influence is linked to the proinflammatory T-helper 1 (Th1) cytokines oranti-inflammatory Th2 cytokines they secrete (
      • Zhou X.
      CD4+ Tcells in atherosclerosis.
      ,
      • Laurat E.
      • Poirier B.
      • Tupin E.
      • Caligiuri G.
      • Hansson G.K.
      • Bariéty M.
      • Nicoletti A.A.
      In vivodownregulation of T helper cell 1 immune responses reduces atherogenesis inapolipoprotein E-knockout mice.
      ,
      • Davenport P.
      • Tipping P.G.
      The role of interleukin-4 and interleukin-12 in theprogression of atherosclerosis in apolipoprotein E-deficient mice.
      ,
      • Daugherty A.
      • Rateri D.L.
      T lymphocytes in atherosclerosis: the yin-yang of Th1 and Th2influences on lesion formation.
      ). Although these cell types constitute the majorcellular players in the current model of atherosclerosis, it has become clearthat other cellular populations of the innate and adaptive immune systems canaffect the disease as well (
      • Getz G.S.
      Thematic reviewseries. The immune system and atherogenesis: immune function in atherogenesis.
      ).In this review, we investigate the involvement of these less prominent leukocytepopulations in atherosclerosis, with the hope of clarifying the role that some ofthese “unusual suspects” may play in the pathogenesis of thisdisease.

      CELLS OF THE INNATE IMMUNE SYSTEM

      Naturalkiller lymphocytes

      The natural killer (NK) cell is a bone marrow-derivedlymphocyte aptly named for its intrinsic ability to lyse certain tumor cells(
      • Herberman R.B.
      • Nunn M.E.
      • Lavrin D.H.
      Natural cytotoxic reactivity of mouse lymphoid cells againstsyngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity.
      ). NK cells are distinct fromboth T- and B-lymphocytes and develop normally in immunocompromised mouse models,such as recombination-activating gene (RAG)-deficient mice (
      • Shinkai Y.
      • Rathbun G.
      • Lam K.P.
      • Oltz E.M.
      • Stewart V.
      • Mendelsohn M.
      • Charron J.
      • Datta M.
      • Young F.
      • Stall A.M.M.
      • et al.
      RAG-2-deficient mice lack mature lymphocytes owing toinability to initiate V(D)J rearrangement.
      ,
      • Mombaerts P.
      • Iacomini J.
      • Johnson R.S.
      • Herrup K.
      • Tonegawa S.
      • Papaioannou V.E.E.
      RAG-1-deficientmice have no mature B and T lymphocytes.
      ), indicating that gene rearrangement is not requiredfor NK cell development. NK cells are an important part of the innate immunesystem. Their primary physiological role is thought to lie in their ability toprovide early defense against pathogens during the initial response period whilethe adaptive immune response is being activated; they are also thought towork in viral surveillance and tumor rejection (
      • Yokoyama W.M.
      • Kim S.
      • French A.R.
      The dynamic life of natural killer cells.
      ). Functionally, these cells act as effectors, eitherthrough cell-mediated cytotoxicity upon the release of dense cytoplasmic granulescontaining perforin and granzymes or through cytokine production, especiallyIFN-γ, thereby activating other effector cells. Cell lysis depends uponperforin forming pores in the cell membrane of target cells, through whichgranzymes (serine proteases) enter the cells and initiate cell death.Additionally, NK cells themselves can become activated through cytokinestimulation. Therefore, NK cells are an important component of the innate immunesystem through target cell killing and cytokine production and have been thoughtto play a role in the developing atherosclerotic plaque as well.
      Directevidence for NK cell involvement in atherogenesis is scant, although someresearchers have localized NK cells to the human atherosclerotic plaque. Adetailed immunohistochemical analysis of autopsy specimens derived from thePathobiological Determinants of Atherosclerosis in Youth Study did find CD56staining of NK cells in the intima of early lesions, but these cells weregenerally low in number and scattered throughout the lesions, found more so inthe shoulder regions than in the necrotic core (
      • Millonig G.
      • Malcom G.T.
      • Wick G.
      Early inflammatory-immunological lesions in juvenileatherosclerosis from the Pathobiological Determinants of Atherosclerosis in Youth(PDAY) Study.
      ). Other immunohistochemical studies examining humanatherosclerotic lesions contributing to aortic and cerebral berry aneurysms havefound NK cells in these plaques and have implicated NK cells in the diseaseprocess itself (
      • Seko Y.
      • Sato O.
      • Takagi A.
      • Tada Y.
      • Matsuo H.
      • Yagita H.
      • Okumura K.
      • Yazaki Y.Y.
      Perforin-secreting killer cell infiltration in the aortic tissue of patients withatherosclerotic aortic aneurysm.
      ,
      • Kosierkiewicz T.A.
      • Factor S.M.
      • W.Dickson D.
      Immunocytochemical studies of atherosclerotic lesionsof cerebral berry aneurysms.
      ). Patients with severe atheroscleroticdisease have higher circulating levels of NK cells (
      • Clerc G.
      • Rouz P.M.
      Lymphocyte subsets in severe atherosclerosis before revascularization.
      ), although a study of elderly patients with peripheralarterial disease found lower NK cell cytotoxicity on a per cell basis along witha similar trend toward an increased number of total circulating NK cells(
      • Bruunsgaard H.
      • Pedersen A.N.
      • Schroll M.
      • Skinhoj P.
      • Pedersen B.K.K.
      Decreased natural killer cellactivity is associated with atherosclerosis in elderly humans.
      ).
      As with humanatherosclerosis, only a few studies have examined NK cells in the mouse-modeleddisease. Immunostaining of atherosclerotic lesions from LDL receptor-deficient(LDLR−/−) mice maintained on a high-fat diet with acarefully titrated asialo-GM1 antibody did show positive staining in early butnot late lesions (
      • Schiller N.K.
      • Boisvert W.A.
      • K.Curtiss L.
      Inflammation in atherosclerosis: lesion formation inLDL receptor-deficient mice with perforin and Lyst(beige) mutations.
      ). WhenLDLR−/− mice were crossed with perforin-deficient mice, nochange in the extent of atherosclerosis was observed, even though NK cellcytolysis was impaired. On the other hand, when LDLR−/−mice were crossed with Lystbeige mutant mice, in which therelease of proteins from the cytoplasmic granules in NK cells is defective, asignificant decrease in atherosclerosis was measured, again in the face ofdefective NK cell cytolysis. When crossing this LDLR−/−Lystbeige model onto a RAG1-deficient background, theatherosclerotic burden actually increased, although this was accompanied by anincrease in plasma total cholesterol levels as well. Puzzling as this may seem,this finding potentially implicates the Lystbeige mutation asproatherogenic in the setting of adaptive immune deficiency, via effects at thevessel wall and/or on lipid metabolism. In other studies using a mouse model oftransplant-associated atherosclerosis, it was determined that NK cells were notinvolved in this process, based on observations usingLystbeige mutant mice as recipients (
      • Shi C.
      • Lee W.S.
      • He Q.
      • Zhang D.
      • Fletcher Jr., D.L.
      • Newell J.B.
      • Haber E.E.
      Immunologic basisof transplant-associated arteriosclerosis.
      ). In interpreting these studies, it is important tonote that NK cells are still present in both the Lystbeigemutant and perforin-deficient models, and despite their defects ingranule-mediated target cell cytolysis, these NK cells may still be capable ofproducing cytokines that modulate the disease process. This notion fits well withthe aforementioned study of NK cells in the elderly, in which decreased cytolysisand increased numbers of circulating NK cells correlated with atherosclerosis(
      • Bruunsgaard H.
      • Pedersen A.N.
      • Schroll M.
      • Skinhoj P.
      • Pedersen B.K.K.
      Decreased natural killer cellactivity is associated with atherosclerosis in elderly humans.
      ).
      There are a number ofchemokines present in the atherosclerotic lesion that may directly influence NKcells. Monocyte chemoattractant protein-1 (MCP-1) functions as a potentchemoattractant for monocytes and T-lymphocytes (
      • Rollins B.J.
      • Yoshimura T.
      • Leonard E.J.
      • Pober J.S.
      Cytokine-activated human endothelial cellssynthesize and secrete a monocyte chemoattractant, MCP-1/JE.
      ,
      • Taub D.D.
      • Proost P.
      • Murphy W.J.
      • Anver M.
      • Longo D.L.
      • Damme J. van
      • Oppenheim J.J.J.
      Monocytechemotactic protein-1 (MCP-1), -2, and -3 are chemotactic for human Tlymphocytes.
      ),is found in the atherosclerotic lesion, and has been shown to be achemoattractant for NK cells as well (
      • Kowala M.C.
      • Recce R.
      • Beyer S.
      • Gu C.
      • Valentine M.
      Characterization of atherosclerosis in LDL receptorknockout mice: macrophage accumulation correlates with rapid and sustainedexpression of aortic MCP-1/JE.
      ). Fractalkine (CX3CL1) is another chemokine found inboth human and murine atherosclerotic lesions via immunohistochemistry(
      • Greaves D.R.
      • Hakkinen T.
      • Lucas A.D.
      • Liddiard K.
      • Jones E.
      • Quinn C.M.
      • Senaratne J.
      • Green F.R.
      • Tyson K.
      • Boyle J.J.
      • et al.
      Linked chromosome 16q13 chemokines, macrophage-derivedchemokine, fractalkine, and thymus- and activation-regulated chemokine, areexpressed in human atherosclerotic lesions.
      ,
      • Lesnik P.
      • Haskell C.A.
      • Charo I.F.
      Decreased atherosclerosis in CX3CR1−/−mice reveals a role for fractalkine in atherogenesis.
      ). Its actions include the induction of NK cellmigration and activation, leading to increased cytotoxicity and the production ofthe proatherogenic cytokine IFN-γ (
      • Umehara H.
      • Bloom E.T.
      • Okazaki T.
      • Nagano Y.
      • Yoshie O.
      • Imai T.T.
      Fractalkine in vascular biology. Frombasic research to clinical disease.
      ). Finally, interleukin-15 (IL-15) is a critical trophicand activating cytokine required for NK cell development. The expression of thiscytokine in both human and murine atherosclerotic plaques (
      • Wuttge D.M.
      • Eriksson P.
      • Sirsjo A.
      • Hansson G.K.
      • Stemme S.
      Expression of interleukin-15 in mouseand human atherosclerotic lesions.
      ) may contribute to the recruitment,maintenance, and activation of NK cells in the atherosclerotic lesion. In short,these cytokines and others capable of NK cell recruitment and activation arepresent in the atherosclerotic lesion, and their atherogenic potential maypartially be linked to NK cell involvement.
      Finally, the most directevidence to date for NK cell involvement in atherosclerosis comes from a recentstudy using a transgenic model overexpressing the inhibitory Ly49A receptor underthe control of the granzyme A promoter (
      • Whitman S.C.
      • Rateri D.L.
      • Szilvassy S.J.
      • Yokoyama W.
      • Daugherty A.A.
      Depletion of natural killercell function decreases atherosclerosis in low-density lipoprotein receptor nullmice.
      ). In this model, any cell type expressing granzyme A(including NK cells) would also express Ly49A on its cell surface, which wouldprevent cell activation when the inhibitory Ly49A receptor interacts with majorhistocompatibility complex (MHC) class I molecules on the target cell (
      • Kim S.
      • Iizuka K.
      • Aguila H.L.
      • Weissman I.L.
      • Yokoyama W.M.
      In vivo natural killer cellactivities revealed by natural killer-deficient mice.
      ). Bone marrow transplantation from thesemice into lethally irradiated LDLR−/− recipients resultedin a profound decrease in atherosclerosis without any changes in plasma lipids,implying that NK cells are proatherogenic. Although intriguing, theinterpretation of these results is complicated, because significant numbers ofnatural killer T-cells (NKT cells), CD8+ cytolytic T-lymphocytes, andother lymphocytes that have the potential to express granzyme A would also beaffected in this system. Regardless, this study supports the notion that NK cellsare involved in the pathogenesis of atherosclerosis, although their specificmechanistic role has yet to be determined.

      Mastcells

      Another component of the innate immune response that has beenimplicated in the pathogenesis of atherosclerosis is the mast cell. Mast cellsare bone marrow-derived cells that reside in connective or mucosal tissues andare involved in inflammation and hypersensitivity reactions. Upon activation,mast cells release the contents of their large cytoplasmic granules that containa number of biologically active agents: vasoactive substances (histamine andleukotrienes), proteolytic enzymes (tryptase and chymase), inflammatory cytokines[tumor necrosis factor-α (TNF-α)], and growth factors[platelet-activating factor (PAF)]. The role of mast cells in atherogenesis islikely to be related to the release of these substances afteractivation.
      Mast cells can be activated in a number of ways. The primarymeans of degranulation occurs when antigen binds to and cross-links surface-boundIgE. In addition, components of the complement cascade known as anaphylotoxins(C3a and C5a) can activate mast cells. Notably, complement is abundant in theatherosclerotic plaque (
      • Niculescu F.
      • Rus H.
      The role of complement activation in atherosclerosis.
      ).Aside from these stimuli, direct neural stimulation (
      • Laine P.
      • Naukkarinen A.
      • Heikkila L.
      • Penttila A.
      • Kovanen P.T.
      Adventitial mast cells connectwith sensory nerve fibers in atherosclerotic coronary arteries.
      ) or excessive cholesterol incorporation into lipidrafts (
      • Baumruker T.
      • Csonga R.
      • Pursch E.
      • Pfeffer A.
      • Urtz N.
      • Sutton S.
      • Bofill-Cardona E.
      • Cooke M.
      • Prieschl E.E.
      Activation of mast cells by incorporation of cholesterol intorafts.
      ) may be involved inactivating mast cells in the plaque as well, although the primary means of mastcell activation in the context of atherosclerosis is stillunknown.
      Although infrequently found in nondiseased arteries, mast cellsare present in human atherosclerotic lesions throughout plaque development,especially in the rupture-prone shoulder regions (
      • Kaartinen M.
      • Penttila A.
      • Kovanen P.T.
      Accumulation of activated mast cells in the shoulder region ofhuman coronary atheroma, the predilection site of atheromatous rupture.
      ,
      • Jeziorska M.
      • McCollum C.
      • Woolley D.E.
      Calcification in atherosclerotic plaque of human carotidarteries: associations with mast cells and macrophages.
      ).This anatomical localization highlights their purported role in promoting plaquerupture and subsequent atherothrombotic events. The proteolytic enzymes chymaseand tryptase may directly degrade matrix components of the fibrous cap, leadingto an unstable plaque phenotype. In addition, these enzymes have been shown tocleave and activate pro-matrix metalloproteinases in carotid arteryatherosclerosis, thereby indirectly leading to matrix degradation and plaqueinstability (
      • Johnson J.L.
      • Jackson C.L.
      • Angelini G.D.
      • George S.J.
      Activation of matrix-degradingmetalloproteinases by mast cell proteases in atherosclerotic plaques.
      ). Finally,heparin proteoglycans and chymase have been shown to inhibit vascular smoothmuscle cell proliferation and collagen synthesis in vitro, supporting the viewthat mast cell activation can lead to plaque instability (
      • Leskinen M.J.
      • Kovanen P.T.
      • A.Lindstedt K.
      Regulation of smooth muscle cell growth, functionand death in vitro by activated mast cells—a potential mechanism for theweakening and rupture of atherosclerotic plaques.
      ).
      Mast cell-derived proteases havealso been implicated in the degradation of lipoproteins, leading to aberrantlipoprotein metabolism and atherogenesis. Chymase can degrade HDL-associatedapolipoproteins involved in reverse cholesterol transport, includingapolipoprotein (apo) A-I, apoE, and apoA-II (
      • Lee M.
      • Uboldi P.
      • Giudice D.
      • Catapano A.L.
      • Kovanen P.T.
      Identification of domains in apoA-Isusceptible to proteolysis by mast cell chymase. Implications for HDL function.
      ,
      • Lee M.
      • Calabresi L.
      • Chiesa G.
      • Franceschini G.
      • Kovanen P.T.
      Mast cell chymase degradesapoE and apoA-II in apoA-I-knockout mouse plasma and reduces its ability topromote cellular cholesterol efflux.
      ).More specifically, chymase degradation of these apolipoproteins inhibitsABCA1-mediated cellular cholesterol efflux while leaving scavenger receptor classB type I-mediated and passive diffusion pathways intact (
      • Favari E.
      • Lee M.
      • Calabresi L.
      • Franceschini G.
      • Zimetti F.
      • Bernini F.
      • Kovanen P.T.T.
      Depletion of pre-beta-high density lipoprotein by human chymase impairsATP-binding cassette transporter A1- but not scavenger receptor class B typeI-mediated lipid efflux to high density lipoprotein.
      ). Furthermore, chymase can also degrade phospholipidtransfer protein, thereby preventing phospholipid transfer to HDL3particles and the subsequent formation of preβ-HDL (
      • Lee M.
      • Metso J.
      • Jauhiainen M.
      • T.Kovanen P.
      Degradation of phospholipid transfer protein (PLTP)and PLTP-generated pre-beta-high density lipoprotein by mast cell chymase impairshigh affinity efflux of cholesterol from macrophage foam cells.
      ). Mast cell degranulation can also lead to LDLdegradation, more specifically apoB-100 proteolysis (
      • Kokkonen J.O.
      • Vartiainen M.
      • T.Kovanen P.
      Low density lipoprotein degradation by secretorygranules of rat mast cells. Sequential degradation of apolipoprotein B by granulechymase and carboxypeptidase A.
      ), which in turn can become a nidus for further LDLmodifications, leading to inflammation and scavenger receptor-mediated uptake.Supporting this notion is the finding that chemical inhibition of chymasesuppressed lipid deposition in the aortas of diet-induced hypercholesterolemichamsters (
      • Uehara Y.
      • Urata H.
      • Ideishi M.
      • Arakawa K.
      • Saku K.
      Chymase inhibition suppresses high-cholesteroldiet-induced lipid accumulation in the hamster aorta.
      ).
      Mast celldegranulation upon activation releases cytokines and vasoactive substances aswell. Immunohistochemical staining of atheromatous coronary arteries shows thatplaque mast cells contain the proinflammatory and atherogenic cytokine TNF-αin preformed secretory granules (
      • Kaartinen M.
      • Penttila A.
      • Kovanen P.T.
      Mast cells in rupture-prone areas of human coronary atheromasproduce and store TNF-alpha.
      ). Activated mast cells can regulate T-cell andmacrophage responses by secreting a number of other cytokines and inflammatoryagents, including MCP-1, the macrophage inflammatory proteins MIP-1α andMIP-1β, and various ILs (IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, andIL-16) (
      • Galli S.J.
      • Gordon J.R.
      • Wershil B.K.
      Cytokine production by mast cells and eosinophils.
      ). Histamine releasefrom activated plaque mast cells constricts muscular arteries, which may accountfor coronary vasospasms that lead to angina or subsequent myocardial infarction(
      • Laine P.
      • Kaartinen M.
      • Penttila A.
      • Panula P.
      • Paavonen T.
      • Kovanen P.T.T.
      Association between myocardialinfarction and the mast cells in the adventitia of the infarct-related coronaryartery.
      ,
      • Huang M.
      • Pang X.
      • Letourneau R.
      • Boucher W.
      • Theoharides T.C.
      Acute stress induces cardiac mast cellactivation and histamine release, effects that are increased in apolipoprotein Eknockout mice.
      ). Histamine increases endothelial permeability in partby inducing the phosphorylation of vascular endothelial cadherin found onvascular endothelial cells (
      • Andriopoulou P.
      • Navarro P.
      • Zanetti A.
      • Lampugnani M.G.
      • Dejana E.
      Histamine induces tyrosinephosphorylation of endothelial cell-to-cell adherens junctions.
      ),which in turn may facilitate the extravasation of lipoproteins and inflammatorycells to atherosclerosis-susceptible regions of the vasculature. On a cellularlevel, histamine can induce proliferation and matrix metalloproteinease-1secretion by smooth muscle cells, enhance the expression of adhesion molecules bystimulated endothelial cells, and regulate the Th1/Th2 polarization ofT-lymphocytes in the plaque (
      • Sasaguri Y.
      • Tanimoto A.
      Role of macrophage-derived histamine inatherosclerosis—chronic participation in the inflammatory response.
      ).Growth factors such as basic fibroblast growth factor are produced by plaque mastcells and may promote plaque progression and neovascularization (
      • Lappalainen H.
      • Laine P.
      • Pentikainen M.O.
      • Sajantila A.
      • Kovanen P.T.T.
      Mast cells in neovascularizedhuman coronary plaques store and secrete basic fibroblast growth factor, a potentangiogenic mediator.
      ). Expression of 5-lipoxygenase by plaquemast cells may not only contribute to the production of the inflammatoryleukotrienes but also may lead to the oxidation of retained lipids, furtherdriving atherogenesis (
      • Spanbroek R.
      • Grabner R.
      • Lotzer K.
      • Hildner M.
      • Urbach A.
      • Ruhling K.
      • Moos M.P.
      • Kaiser B.
      • Cohnert T.U.
      • Wahlers T.T.
      • et al.
      Expanding expression of the 5-lipoxygenase pathwaywithin the arterial wall during human atherogenesis.
      ).Finally, mast cells appear to be associated with the process of vascularcalcification seen in advanced plaques (
      • Jeziorska M.
      • McCollum C.
      • Woolley D.E.
      Calcification in atherosclerotic plaque of human carotidarteries: associations with mast cells and macrophages.
      ). Therefore, there is increasing evidence that mastcells are not only present in the atherosclerotic plaque but also may help drivethe inflammatory response that characterizes thisdisease.

      Neutrophils

      The neutrophil is the most commontype of leukocyte found in the circulation and is a major component of the innateimmune response. These short-lived phagocytic cells are involved primarily inacute inflammation by engulfing damaged tissue and bacteria, killing invadingmicrobes through the respiratory burst, and secreting proteolytic enzymes such asneutrophil elastase and matrix metalloproteinases. A number of epidemiologicaland clinical studies have found leukocytosis in general and specificallyincreased levels of neutrophils in the circulation to be an independent riskfactor for coronary heart disease (
      • Madjid M.
      • Awan I.
      • Willerson J.T.
      • W.Casscells S.
      Leukocyte count and coronary heart disease:implications for risk assessment.
      ). Although neutrophils generally are not detected instable atherosclerotic plaques, they are prevalent in eroded or ruptured plaquesobtained from patients with acute coronary syndromes (
      • Naruko T.
      • Ueda M.
      • Haze K.
      • van der Wal A.C.
      • van der Loos C.M.
      • Itoh A.
      • Komatsu R.
      • Ikura Y.
      • Ogami M.
      • Shimada Y.Y.
      • et al.
      Neutrophil infiltration of culprit lesions in acute coronarysyndromes.
      ). At this time, it is unclear whether the proteinasessecreted by recruited neutrophil lead to plaque erosion and rupture or whetherthese cells just accumulate at the site of tissue damage, especially given thatthese matrix-degrading enzymes are also synthesized by other cell types in theplaque, namely macrophages and smooth muscle cells (
      • Dollery C.M.
      • McEwan J.R.
      • Henney A.M.
      Matrix metalloproteinases and cardiovascular disease.
      ,
      • Owen C.A.
      • Campbell E.J.
      The cell biology of leukocyte-mediated proteolysis.
      ,
      • Dollery C.M.
      • Owen C.A.
      • Sukhova G.K.
      • Krettek A.
      • Shapiro S.D.
      • Libby P.P.
      Neutrophil elastase inhuman atherosclerotic plaques. Production by macrophages.
      ) and possibly mast cells as well. Activated neutrophilsalso secrete myeloperoxidases, which may contribute to atherosclerosis byoxidizing LDL, leading to uptake by macrophages (
      • Podrez E.A.
      • Schmitt D.
      • Hoff H.F.
      • L.Hazen S.
      Myeloperoxidase-generated reactive nitrogen speciesconvert LDL into an atherogenic form in vitro.
      ) as well as by modifying apoA-I and thereby attenuatingABCA1-dependent cholesterol efflux (
      • Bergt C.
      • Pennathur S.
      • Fu X.
      • Byun J.
      • O'Brien K.
      • McDonald T.O.
      • Singh P.
      • Anantharamaiah G.M.
      • Chait A.
      • Brunzell J.J.
      • et al.
      The myeloperoxidase product hypochlorous acidoxidizes HDL in the artery wall and impairs ABCA1-dependent cholesteroltransport.
      ).

      CELLS THAT BRIDGE THE INNATEAND ADAPTIVE IMMUNE RESPONSES

      Dendritic cells

      As discussedabove, the inflammatory response to retained and modified lipids in the vesselwall is the hallmark of the atherosclerotic lesion. An important initial step inthis inflammatory cascade is the processing and proper presentation of theputative plaque antigens to the T-lymphocytes that participate in atherogenesis.Recent work has shown that the dendritic cell may be an important regulator ofthis inflammatory response by acting as an efficient antigen-presentingcell.
      Dendritic cells initially described by Steinman and Cohn (
      • Steinman R.M.
      • Cohn Z.A.
      Identification of a novel cell type in peripheral lymphoidorgans of mice. I. Morphology, quantitation, tissue distribution.
      ) are professional antigen-presentingcells that are able to initiate primary immune responses. Although dendriticcells as a family are heterogeneous and functionally diverse, these bonemarrow-derived cells arise from a common CD34+ progenitor and progressfunctionally through different stages of development. Dendritic cells are able toregulate the immune response to foreign and self-antigens and therefore areimportant in either initiating an adaptive immune response or inducing tolerance(
      • Kis Z.
      • Pallinger E.
      • Endresz V.
      • Burian K.
      • Jelinek I.
      • Gonczol E.
      • Valyi-Najy I.I.
      The interactionsbetween human dendritic cells and microbes: possible clinical applications ofdendritic cells.
      ). To generalize dendriticcell maturation, immature dendritic cells efficiently sample their antigenicmicroenvironment through macropinocytosis and receptor-mediated endocytosis.Activating signals transmitted largely by the diverse complement of Toll-likereceptors expressed by dendritic cells induce maturation (
      • Iwasaki A.
      • Medzhitov R.
      Toll-like receptor control of the adaptive immune responses.
      ). This functional change is characterizedby a downregulation of the endocytic machinery and an upregulation of theexpression of antigen-presentation molecules (MHC I and II, CD1), costimulatorymolecules (CD40, CD80/B7.1, CD86/B7.2), and the secretion of inflammatorycytokines (such as IL-12 and TNF-α) (
      • Iwasaki A.
      • Medzhitov R.
      Toll-like receptor control of the adaptive immune responses.
      ). This phenotypic switch facilitates the interactionwith and subsequent activation of T-lymphocytes, initiating the adaptive immuneresponse (
      • Bobryshev Y.V.
      Dendriticcells and their involvement in atherosclerosis.
      ).
      Dendriticcells are a component of the proposed vessel-associated lymphoid tissue and arefound in the intima of susceptible arteries before atherosclerotic lesiondevelopment (
      • Wick G.
      • Romen M.
      • Amberger A.
      • Metzler B.
      • Mayr M.
      • Falkensammer G.
      • Xu Q.Q.
      Atherosclerosis,autoimmunity, and vascular-associated lymphoid tissue.
      ). Monocyteprecursors of macrophages and dendritic cells are also recruited to the growingplaque by the activated endothelium throughout atherogenesis (
      • Weis M.
      • Schlichting C.L.
      • Engleman E.G.
      • Cooke J.P.
      Endothelial determinants of dendritic celladhesion and migration: new implications for vascular diseases.
      ). Dendritic cells have been identified inthe atherosclerotic plaques of both humans and mice by immunohistochemical andPCR-based approaches, implicating them in the pathogenesis of the disease(
      • Soilleux E.J.
      • Morris L.S.
      • Trowsdale J.
      • Coleman N.
      • Boyle J.J.J.
      Human atherosclerotic plaquesexpress DC-SIGN, a novel protein found on dendritic cells and macrophages.
      ,
      • Bobryshev Y.V.
      • Babaev V.R.
      • Iwasa S.
      • Lord R.S.
      • Watanabe T.
      Atherosclerotic lesions ofapolipoprotein E deficient mice contain cells expressing S100 protein.
      ,
      • Bobryshev Y.V.
      • Taksir T.
      • Lord R.S.
      • Freeman M.W.
      Evidence that dendritic cells infiltrateatherosclerotic lesions in apolipoprotein E-deficient mice.
      ). Dendritic cells colocalize withT-lymphocytes in the shoulder regions of rupture-prone atherosclerotic plaques(
      • Yilmaz A.
      • Lochno M.
      • Traeg F.
      • Cicha I.
      • Reiss C.
      • Stumpf C.
      • Raaz D.
      • Anger T.
      • Amann K.
      • Probst T.T.
      • et al.
      Emergence of dendritic cells in rupture-prone regions ofvulnerable carotid plaques.
      ), suggesting that antigenpresentation and costimulation by plaque dendritic cells lead to the activationof T-lymphocytes at this site, which may ultimately contribute to plaquedestabilization and subsequent atherothrombosis. Dendritic cells in the vesselwall also express components of the complement system, namely C1q, which likelyfacilitate the capture of immune complexes in the atheroma (
      • Cao W.
      • Bobryshev Y.V.
      • Lord R.S.
      • Oakley R.E.
      • Lee S.H.
      • Lu J.J.
      Dendritic cells in the arterialwall express C1q: potential significance in atherogenesis.
      ).
      Modified lipids present inatherosclerosis have been shown to influence dendritic cell maturation andactivation in vitro. Oxidized low density lipoprotein (OxLDL) not only promotesmonocyte to dendritic cell maturation (
      • Perrin-Cocon L.
      • Coutant F.
      • Agaugue S.
      • Deforges S.
      • Andre P.
      • Lotteau V.V.
      Oxidized low-densitylipoprotein promotes mature dendritic cell transition from differentiatingmonocyte.
      ) but also increases the expression ofantigen-presenting and costimulatory molecules on the mature dendritic cell(
      • Alderman C.J.J.
      • Bunyard P.R.
      • Chain B.M.
      • Foreman J.C.
      • Leake D.S.
      • Katz D.R.R.
      Effects ofoxidised low density lipoprotein on dendritic cells: a possible immunoregulatorycomponent of the atherogenic micro-environment?.
      ). One of the modified lipidsgenerated during the oxidative process is lysophosphatidylcholine, which mayinduce dendritic cell maturation directly through G-protein-coupled receptorsignaling (
      • Coutant F.
      • Perrin-Cocon L.
      • Agaugue S.
      • Delair T.
      • Andre P.
      • Lotteau V.V.
      Mature dendritic cellgeneration promoted by lysophosphatidylcholine.
      ) or indirectly bypreventing the maturation block mediated by peroxisome proliferator-activatedreceptor γ signaling (
      • Coutant F.
      • Agaugue S.
      • Perrin-Cocon L.
      • Andre P.
      • Lotteau V.
      Sensing environmental lipids bydendritic cell modulates its function.
      ).The liberation of signaling phospholipids by secretory phospholipaseA2 has also been implicated in dendritic cell maturation (
      • Perrin-Cocon L.
      • Agaugue S.
      • Coutant F.
      • Masurel A.
      • Bezzine S.
      • Lambeau G.
      • Andre P.
      • Lotteau V.V.
      Secretory phospholipase A2 induces dendritic cell maturation.
      ). On the other hand, the maturation andantigen-presentation ability of dendritic cells can be inhibited by statins(
      • Yilmaz A.
      • Reiss C.
      • Tantawi O.
      • Weng A.
      • Stumpf C.
      • Raaz D.
      • Ludwig J.
      • Berger T.
      • Steinkasserer A.
      • Daniel W.G.G.
      • et al.
      HMG-CoA reductase inhibitors suppress maturation of humandendritic cells: new implications for atherosclerosis.
      ), the cholesterol-loweringclass of drugs that has been found to have a number of immunomodulatory effectsas well. Dendritic cells treated with polyunsaturated fatty acids of the n-3 andn-6 family also display a maturation block when challenged withlipopolysaccharide, suggesting that part of the reported anti-inflammatory andatheroprotective effect of these dietary fatty acids (
      • Lada A.T.
      • Rudel L.L.
      Dietary monounsaturated versus polyunsaturated fatty acids: which is reallybetter for protection from coronary heart disease?.
      ,
      • Laaksonen D.E.
      • Nyyssonen K.
      • Niskanen L.
      • Rissanen T.H.
      • Salonen J.T.T.
      Prediction of cardiovascularmortality in middle-aged men by dietary and serum linoleic and polyunsaturatedfatty acids.
      )may be linked to preventing dendritic cell activation (

      Zeyda, M., M. D. Saemann, K. M. Stuhlmeier, D.G. Mascher, P. N. Nowotny, G. J. Zlabinger, W. Waldhausl, and T. M. Stulnig.2005. Polyunsaturated fatty acids block dendritic cell activation and functionindependently of NF-B activation. J. Biol. Chem. Epub ahead of print. January 31, 2005; doi:10.1074/jbs.M410000200.

      ). Finally, recent studies have identified other lipidmediators that may be responsible for retaining dendritic cells in theatherosclerotic plaque, namely PAF and 18:1 lysophosphatidic acid (
      • Llodra J.
      • Angeli V.
      • Liu J.
      • Trogan E.
      • Fisher E.A.
      • Randolph G.J.J.
      Emigration of monocyte-derivedcells from atherosclerotic lesions characterized regressive, but not progressive,plaques.
      ,
      • Angeli V.
      • Llodra J.
      • Rong J.X.
      • Satoh K.
      • Ishii S.
      • Shimizu T.
      • Fisher E.A.
      • Randolph G.J.J.
      Dyslipidemia associated with atherosclerotic disease systemically altersdendritic cell mobilization.
      ). By preventing dendritic cells from leaving theplaque, these lipid mediators contribute to both continued plaque growth and thelesional localization of the inflammatory response to plaque antigens.Interestingly, HDL-associated PAF acetylhydrolase can inhibit this dendritic cellretention (
      • Angeli V.
      • Llodra J.
      • Rong J.X.
      • Satoh K.
      • Ishii S.
      • Shimizu T.
      • Fisher E.A.
      • Randolph G.J.J.
      Dyslipidemia associated with atherosclerotic disease systemically altersdendritic cell mobilization.
      ), highlightinganother atheroprotective attribute of HDL.
      Other recognized risk factorsfor atherosclerosis may also directly influence dendritic cell biology in theplaque. Nicotine as a major component of cigarette smoke is able todose-dependently activate dendritic cells, leading to increased Th1 cytokinesecretion by T-cells (
      • Aicher A.
      • Heeschen C.
      • Mohaupt M.
      • Cooke J.P.
      • Zeiher A.M.
      • Dimmeler S.S.
      Nicotine stronglyactivates dendritic cell-mediated adaptive immunity: potential role forprogression of atherosclerotic lesions.
      ). On theother hand, the nonenzymatic glycation of proteins that occur in the setting ofdiabetes appears to promote dendritic cell maturation but prevents theirexpression of costimulatory molecules and their ability to activate T-cells(
      • Price C.L.
      • Sharp P.S.
      • North M.E.
      • Rainbow S.J.
      • Knight S.C.C.
      Advanced glycation end productsmodulate the maturation and function of peripheral blood dendritic cells.
      ). Finally, dendritic cellsmay play an important role in the inflammation induced by infectious agents inthe vessel wall, another potential contributor to atherogenesis (
      • Kis Z.
      • Pallinger E.
      • Endresz V.
      • Burian K.
      • Jelinek I.
      • Gonczol E.
      • Valyi-Najy I.I.
      The interactionsbetween human dendritic cells and microbes: possible clinical applications ofdendritic cells.
      ,
      • Bobryshev Y.V.
      • Cao W.
      • Phoon M.C.
      • Tran D.
      • Chow V.T.K.
      • Lord R.S.A.
      • Lu J.J.
      Detection ofChlamydophila pneumoniae in dendritic cells in atherosclerotic lesions.
      ).

      γδT-lymphocytes

      T-cells are members of the adaptive immune response thatrespond to specific antigens that complement their rearranged T-cell receptor(TCR). Although the majority of T-lymphocytes express the αβ TCR, anothersubset of T-cells exist that bear the γδ type of TCR. These cellsrepresent less than 5% of the T-cell population in the peripheral human blood,although they are enriched in specific tissues, including the gastrointestinalmucosa, skin, and splenic pulp, as well as at sites of chronic inflammation, suchas the joint synovium in rheumatoid arthritis (
      • Carding S.R.
      • Egan P.J.
      γδ T cells: functional plasticity and heterogeneity.
      ). γδ T-cells have limited TCR diversity, arethought to be important for the initial defense against epidermal and mucosalpathogens, and can either activate or suppress other lymphocyte subsets(
      • Hayday A.
      • Tigelaar R.
      Immunoregulation in the tissues by γδ T cells.
      ). This immunomodulatoryfunction stems largely from the cytokines they produce, which include both Th1and Th2 types, namely IL-2, IL-4, IL-5, IL-10, and IFN-γ (
      • Aljurf M.
      • Ezzat A.
      • Musa M. O.
      Emerging role of gammadelta T-cells in health and disease.
      ). In contrast with traditional αβT-cells, some γδ T-cells do not require antigen processing andpresentation in the context of MHC molecules to respond to their cognate antigens(
      • Aljurf M.
      • Ezzat A.
      • Musa M. O.
      Emerging role of gammadelta T-cells in health and disease.
      ). This unique property ofγδT-cells to rapidly respond to free antigen positions these cells asbridging lymphocytes between the innate and adaptive immune responses. γδT-cells have been detected in the intima of human atherosclerotic lesions,especially in the early stages of lesion formation (
      • Millonig G.
      • Malcom G.T.
      • Wick G.
      Early inflammatory-immunological lesions in juvenileatherosclerosis from the Pathobiological Determinants of Atherosclerosis in Youth(PDAY) Study.
      ,
      • Kleindienst R.
      • Xu Q.
      • Willeit J.
      • Waldenberger F.R.
      • Weimann S.
      • Wick G.G.
      Demonstration of heatshock protein 60 expression and T lymphocytes bearing αβ or γδreceptor in human atherosclerotic lesions.
      ).In the lesions of LDLR−/− andapoE−/− mice, transcripts for the γ-TCR chain havebeen identified using laser-capture microdissection with subsequent RNA isolationand RT-PCR analysis (P. A. VanderLaan, C. A. Reardon, and G. S. Getz, unpublisheddata). The role of γδ T-cells in atherosclerosis remains unclear, butoverall these cells may be proatherogenic, because the absence of γδT-cells led to a 15% reduction in plasma total cholesterol levels and a 21%reduction in aortic sinus atherosclerosis in 18 week oldapoE−/−/TCRδ−/− mice, althoughthese differences did not achieve statistical significance (
      • Elhage E.
      • Gourdy P.
      • Brouchet L.
      • Jawien J.
      • Fouque M-J.
      • Fiévet C.
      • Huc X.
      • Bareira Y.
      • Couloumiers J.C.
      • Arnal J.F.F.
      • et al.
      Deleting TCRαβ+ orCD4+ T lymphocytes leads to opposite effects on site-specificatherosclerosis in female apolipoprotein E-deficient mice.
      ).

      NKTlymphocytes

      It is becoming very clear that the chronic inflammation ofatherosclerosis encompasses components of both innate and adaptive immunity(
      • Getz G.S.
      Thematic reviewseries. The immune system and atherogenesis: immune function in atherogenesis.
      ). To understand thisinterconnection, one cell type in particular warrants further investigation: theNKT lymphocyte. NKT cells are a subset of lymphocytes characterized by thecoexpression of both NK cell markers (NK1.1/CD161) and a functional TCR complex.The most intriguing property of NKT cells from the standpoint of atherosclerosisresearchers is their ability to recognize lipid and glycolipid antigens presentedon CD1d molecules by their semi-invariant TCR (predominantlyVα14Jα18/Vβ8 for mice and Vα24Jα18/Vβ11 for humans). CD1molecules are a family of nonpolymorphic cell surface glycoproteins expressed bycertain antigen-presenting cells and have structural and functional similaritiesto MHC proteins (
      • Park S.H.
      • Bendelac A.
      CD1-restricted T-cell responses and microbial infection.
      ). Although anumber of bacterial glycolipids, such as phosphoinositol mannosides,lipoarabinomannan, mycolic acids, and hexosyl-1-phosphoisoprenoids, have beenfound to be presented by CD1 molecules, endogenous antigens for CD1d remainlargely unknown (
      • Schiable U.E.
      • Kaufmann S.H.E.
      CD1 and CD1-restricted T cells in infections withintracellular bacteria.
      ), althoughrecently Bendelac and colleagues (
      • Zhou D.
      • Mattner J.
      • Cantu C.
      • Schrantz N.
      • Yin N.
      • Gao Y.
      • Sagiv Y.
      • Hudspeth K.
      • Wu Y.P.
      • Yamashita T.T.
      • et al.
      Lysosomal glycosphingolipid recognition by NKT cells.
      ) identified the lysosomal glycosphingolipidisoglobotrihexosylceramide as a potential endogenous ligand for both human andmurine NKT cells. Experimentally, this lack of activating endogenous antigens hasbeen bypassed by using the synthetic ligand α-galactosylceramide(α-GalCer) derived from marine sponges to study NKT cell physiology.α-GalCer specifically and robustly activates NKT cells in a CD1d-dependentmanner when processed and presented by antigen-presenting cells (
      • Skold M.
      • Behar S.M.
      Role of CD1d-restricted NKT cells in microbial immunity.
      ).
      Because NKT cells share manycharacteristics of both NK cells (innate immunity) and T-cells (adaptiveimmunity), this lymphocyte in particular is positioned as an immunomodulator bybridging the gap between these distinct phases of the early and late immuneresponse. The cross-talk between NKT cells and other lymphocytes has beendescribed previously. In mice, specific activation of NKT cells resulted inconcomitant cytokine production by NK cells and the expression of the activationmarker CD69 by NK cells, B-lymphocytes, and CD8+ T-lymphocytes in vivo(
      • Carnaud C.
      • Lee D.
      • Donnars O.
      • Park S.H.
      • Beavis A.
      • Koezuka Y.
      • Bendelac A.A.
      Cutting edge. Cross talkbetween cells of the innate immune system: NKT cells rapidly activate NK cells.
      ). Furthermore, NKT cells havealso been shown to directly promote B-lymphocyte proliferation and antibodyproduction in vitro (
      • Galli G.
      • Nuti S.
      • Tavarini S.
      • Galli-Stampino L.
      • Lalla C. De
      • Casorati G.
      • Dellabona P.
      • Abrignani S.S.
      CD1d-restricted help to B cells by human invariant naturalkiller T lymphocytes.
      ,
      • Galli G.
      • Nuti S.
      • Tavarini S.
      • Galli-Stampino L.
      • Lalla C. De
      • Casorati G.
      • Dellabona P.
      • Abrignani S.S.
      Innate immune responses support adaptive immunity: NKT cellsinduce B cell activation.
      ). In all cases, theseeffects were found to be CD1d-dependent, highlighting the importance of theCD1d-TCR interaction in NKT cell activation.
      Because one of the earliestevents in the pathogenesis of atherosclerosis is the retention and subsequentoxidative modification of lipids and lipoproteins in the vessel wall, it followsthat the NKT cell may be involved in reacting to these lipid neoantigens in theplaque when presented on CD1 molecules by either macrophages or dendritic cells.In fact, glycosphingolipids and gangliosides have been identified in humanatherosclerotic tissue, and increases in plasma cholesterol levels are associatedwith increased glycosphingolipids as well (
      • Garner B.
      • Priestman D.A.
      • Stocker R.
      • Harvey D.J.
      • Butters T.D.
      • Platt F.M.M.
      Increasedglycosphingolipid levels in serum and aortae of apolipoprotein E gene knockoutmice.
      ,
      • Senn H.J.
      • Orth M.
      • Fitzke E.
      • Koster W.
      • Wieland H.
      • Gerok W.
      Human serum gangliosides inhypercholesterolemia, before and after extracorporeal elimination of LDL.
      ,
      • Bobryshev Y.V.
      • Lord R.S.
      • Golovanova N.K.
      • Gracheva E.V.
      • Zvezdina N.D.
      • Prokazova N.V.V.
      Phenotype determination of anti-GM3 positive cells inatherosclerotic lesions of the human aorta. Hypothetical role of ganglioside GM3in foam cell formation.
      ). In apoE−/− mice, multiplegangliosides have been extracted from the diseased vessel wall, and plasma levelsof gangliosides were increased by 7-fold compared with those of wild-typecontrols (
      • Garner B.
      • Priestman D.A.
      • Stocker R.
      • Harvey D.J.
      • Butters T.D.
      • Platt F.M.M.
      Increasedglycosphingolipid levels in serum and aortae of apolipoprotein E gene knockoutmice.
      ). Therefore, it isattractive to hypothesize that NKT cells may be activated by modified lipidantigens either present in or induced by oxidized lipoproteins.
      Directevidence for NKT cell involvement in atherosclerosis is limited to a handful ofstudies. In human atherosclerotic lesions, macrophage foam cells have been shownto strongly express all four human CD1 proteins (CD1a, -b, -c, and -d)(
      • Melian A.
      • Geng Y-J.
      • Sukhova G.K.
      • Libby P.
      • Porcelli S.A.
      CD1 expression in humanatherosclerosis. A potential mechanism for T cell activation by foam cells.
      ). In patients with bothstable and unstable angina, a decrease in the number of circulating NKT cells wasobserved. One possible explanation for this finding is that once the NKT cellsare activated, they secrete IFN-γ and subsequently undergo apoptosis, thusaccounting for the decreased numbers of these cells in the circulation(
      • Fujii S.
      • Ando Y.
      • Naya M.
      • Ohmura K.
      • Nakai Y.
      • Mishima Y.
      • Iwabuchi K.
      • Onoe K.
      • Yamashita T.
      • Makiguchi M.M.
      Diverse activation of natural killer T cells andperforin-producing CD4 T cells in stable angina versus unstable angina(Abstract).
      ). On the other hand, it wasrecently reported that activation of NKT cells does not necessarily lead toapoptosis but instead can result in a downregulation of the TCR and NK1.1/CD161to prevent overstimulation (
      • Wilson M.T.
      • Johansson C.
      • Olivares-Villagomez D.
      • Singh A.K.
      • Stanic A.K.
      • Wang C-R.
      • Joyce S.
      • Wick M.J.
      • Van Kaer L.L.
      The response of natural killer T cells toglycolipid antigens is characterized by surface receptor down-modulation andexpansion.
      ). In the lesions of LDLR−/− andapoE−/− mice, transcripts for the semi-invariant TCR(Vα14Jα18) have been identified using laser-capture microdissection withsubsequent RNA isolation and RT-PCR analysis (P. A. VanderLaan, C. A. Reardon,and G. S. Getz, unpublished data). In apoE−/− mice,exogenous administration of lipopolysaccharide increased both the extent ofatherosclerotic lesions and the numbers of circulating and plaque NKT cells(
      • Ostos M.A.
      • Recalde D.
      • Zakin M.M.
      • Scott-Algara D.
      Implication of natural killer T cells inatherosclerosis development during a LPS-induced chronic inflammation.
      ). Exogenous administrationof α-GalCer increased atherosclerosis in apoE−/− mice,whereas CD1d-deficient mice showed reduced atherosclerotic lesion development(
      • Tupin E.
      • Nicoletti A.
      • Elhage R.
      • Rudling M.
      • Ljunggren H.G.
      • Hansson G.K.
      • Berne G.P.P.
      CD1d-dependent activation of NKT cells aggravates atherosclerosis.
      ,
      • Nakai Y.
      • Iwabuchi K.
      • Fujii S.
      • Ishimori N.
      • Dashtsoodol N.
      • Watano K.
      • Mishima T.
      • Iwabuchi C.
      • Tanaka S.
      • Bezbradica J.S.S.
      • et al.
      Natural killer T cells accelerate atherogenesis inmice.
      ,
      • Major A.S.
      • Wilson M.T.
      • McCaleb J.L.
      • Su Y.R.
      • Stanic A.K.
      • Joyce S.
      • Kaer L. Van
      • Fazio S.
      • Linton M.M.
      Quantitative and qualitative differences in proatherogenic NKTcells in apolipoprotein E-deficient mice.
      ). This α-GalCer-driven increase inatherosclerosis was accompanied by a dramatic release of both the atherogeniccytokine IFN-γ as well as IL-4 by NKT cells (
      • Major A.S.
      • Wilson M.T.
      • McCaleb J.L.
      • Su Y.R.
      • Stanic A.K.
      • Joyce S.
      • Kaer L. Van
      • Fazio S.
      • Linton M.M.
      Quantitative and qualitative differences in proatherogenic NKTcells in apolipoprotein E-deficient mice.
      ). Interestingly, it has been shown that a genderdimorphism exists with respect to α-GalCer-induced cytokine secretion, withsignificantly higher levels of IFN-γ achieved in the serum of females versusmales, whereas there was no difference in IL-4 levels (
      • Gourdy P.
      • Araujo L.M.
      • Zhu R.
      • Garmy-Susini B.
      • Diem S.
      • Laurell H.
      • Leite-De-Moraes M.
      • Dy M.
      • Arnal J.F.
      • Bayard F.F.
      • et al.
      Relevance of sexual dimorphism to regulatory Tcells: estradiol promotes IFN-gamma production by invariant natural killer Tcells.
      ). In vitro experiments have shown that macrophagesincubated with oxidized LDL display increased expression of CD1d, which in turncan induce NKT cells to produce IFN-γ (
      • Nakai Y.
      • Iwabuchi K.
      • Fujii S.
      • Ishimori N.
      • Dashtsoodol N.
      • Watano K.
      • Mishima T.
      • Iwabuchi C.
      • Tanaka S.
      • Bezbradica J.S.S.
      • et al.
      Natural killer T cells accelerate atherogenesis inmice.
      ). Finally, a recent study not only suggested that NKTcell involvement in atherogenesis is mostly limited to the early fatty streaklesions with little effect on larger and more advanced lesions but also foundthat the absence of NKT cells did not significantly alter cytokine mRNA levels inthe vessel wall (
      • Aslanian A.M.
      • Chapman H.A.
      • F.Charo I.
      Transient role for CD1d-restricted natural killer Tcells in the formation of atherosclerotic lesions.
      ). Animportant point here is that all the aforementioned experiments were performed inthe presence of an otherwise functional immune system; therefore, theproatherogenic potential of NKT cells may be attributable to their interactionswith other lymphocytes present either in the plaque itself or in other lymphoidcompartments. In any case, at this time it appears that CD1d-mediated activationof NKT cells results either directly or indirectly in an inflammatory cytokineexpression profile that drives the progression of atherosclerotic lesiondevelopment.

      CELLS OF THE ADAPTIVE IMMUNESYSTEM

      Regulatory T-lymphocytes

      Regulatory T-cells(Treg) are a somewhat heterogeneous subset of CD4+ T-cellsthat can suppress inflammation and induce tolerance, thereby modulating theadaptive immune response (
      • O'Garra A.
      • Vieira P.L.
      • Vieira P.
      • Goldfield A.E.
      IL-10-producing and naturally occurringCD4+ Tregs: limiting collateral damage.
      ).Through either cytokine secretion (including IL-10 and transforming growthfactor-β) or direct cellular interactions, Treg can exert theirimmunosuppressive functions by inhibiting the proliferation of naïve T-cellsas well as reducing both Th1- and Th2-biased responses. In a recent study,ovalbumin-specific T-regulatory type 1 cells were generated in vitro andadoptively transferred into apoE−/− mice that were alsoimmunized with ovalbumin (
      • Mallat Z.
      • Gojova A.
      • Brun V.
      • Esposito B.
      • Fournier N.
      • Cottrez F.
      • Tedgui A.
      • Groux H.H.
      Induction ofa regulatory T cell type 1 response reduces the development of atherosclerosis inapolipoprotein E-knockout mice.
      ).This resulted in a reduction in the amount of atherosclerosis in the thoracicaorta and the aortic sinus without any change in plasma cholesterol levels. Inaddition, the composition of the aortic sinus lesions was altered, with areduction in the number of macrophages and T-cells but not smooth muscle cells.Intense IL-10 staining was detected in the aortic sinus lesions viaimmunohistochemistry. However, it is not clear whether these lesion differenceswere mediated directly by IL-10 or indirectly by the suppression of both Th1 andTh2 responses, as suggested by the decreased production of both the Th1 cytokineIFN-γ and the Th2 cytokines IL-4 and IL-5 by T-cells isolated from theadoptively transferred mice. Regardless, the ability of these cells to modulatethe immune response makes them attractive therapeutic targets in preventingatherosclerosis.

      B-lymphocytes

      Experimentally, B-cellsas a group have been shown to be atheroprotective, because eliminating themeither genetically (
      • Major A.S.
      • Fazio F.
      • Linton M.F.
      B-lymphocyte deficiency increases atherosclerosis inLDL-receptor-null mice.
      ) or throughsplenectomy (
      • Caligiuri G.
      • Nicoletti A.
      • Poirier B.
      • Hansson G.K.
      Protective immunity against atherosclerosiscarried by B cells of hypercholesterolemic mice.
      ) increasesatherosclerosis. Although B-lymphocytes generally are not detected inatherosclerotic lesions (
      • Jonasson L.
      • Holm J.
      • Skalli O.
      • Bondjers G.
      • Hansson G.K.
      Regional accumulation of T cells,macrophages, and smooth muscle cells in the human atherosclerotic plaque.
      ,
      • Munro J.M.
      • van der Walt J.D.
      • Munro C.S.
      • Chalmers J.A.
      • Cox E.L.L.
      An immunohistochemical analysisof human aortic fatty streaks.
      ), an adventitiallocalization of these cells may partially explain their demonstrated influence onplaque development (
      • Ramshaw A.L.
      • Parums D.V.
      Immunohistochemical characterization of inflammatory cellsassociated with advanced atherosclerosis.
      ,
      • Aubry M.C.
      • Riehle D.L.
      • Edwards W.D.
      • Maradit-Kremers H.
      • Roger V.L.
      • Sebo T.J.
      • Gabriel S.E.E.
      B-lymphocytes in plaque and adventitia of coronary arteries in two patients withrheumatoid arthritis and coronary atherosclerosis: preliminary observations.
      ). On the other hand, themajor immunological product of B-cells, immunoglobulins, is readily identified inthe plaque throughout lesion development (
      • Yla-Herttuala S.
      • Palinski W.
      • Butler S.W.
      • Picard S.
      • Steinberg D.
      • Witztum J.L.L.
      Rabbit and humanatherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL.
      ,
      • Sako T.
      • Uchida E.
      • Kagawa Y.
      • Hirayama K.
      • Takahashi T.
      • Nakade T.
      • Niiyama M.
      • Izumisawa Y.
      • Taniyama H.H.
      Immunohistochemical detection of apolipoprotein B-100 andimmunoglobulins (IgA, IgM, IgG) in the splenic arteries of aging dogs.
      ). Antibodies that recognize OxLDL have been found inthe circulation of both humans and mice (
      • Palinski W.
      • Witztum J.L.
      Immune responses to oxidative neoepitopes on LDL andphospholipids modulate the development of atherosclerosis.
      ,
      • Lefvert A.K.
      Heterogeneity of autoantibodies against cardiolipin and oxidatively modified LDLsrevealed by human monoclonal antibodies.
      ). This has focused attention on the role that asubpopulation of innate B-cells namely B-1 B-lymphocytes, may play inatherogenesis, which will be covered extensively by Witztum and colleagues in aseparate review in this series. In total, most studies to date suggest thatB-lymphocytes in general are antiatherogenic on the basis of the protectiveantibodies they produce, but it is important to consider other roles that B-cellsmay play in modulating the atherosclerotic immune response, namely throughantigen presentation and cytokine secretion.
      B-cells are able toselectively internalize their cognate antigen via the B-cell receptor, whichmakes B-cells extremely efficient at presenting their respective antigens toT-cells. B-cells also express costimulatory molecules, enabling them to activateT-cells that also recognize the same antigen, thereby initiating and amplifyingthe immune response (
      • Lund F.E.
      • Garvy B.A.
      • Randall T.D.
      • Harris D.P.
      Regulatory roles for cytokine-producing B cellsin infection and autoimmune disease.
      ). Forthis reason, B-cells should be considered along with the other antigen-presentingcells involved in atherosclerosis, macrophages and dendritic cells. B-cellsisolated from the spleens of aged apoE−/− mice withsubstantial atherosclerotic lesions had significantly increased expression of thecostimulatory molecules CD80/B7.1 and CD86/B7.2 compared with B-cells from eitheryounger apoE−/− mice devoid of atherosclerosis orage-matched C57BL/6 controls (
      • Afek A.
      • Harats D.
      • Roth A.
      • Keren G.
      • George J.
      Evidence for the involvement of T cell costimulationthrough the B-7/CD28 pathway in atherosclerotic plaques from apolipoprotein Eknockout mice.
      ). Furthermore, increased numbers of circulatingactivated B-cells expressing CD80 positively correlate with the severity ofcarotid atherosclerosis as assessed by intima-media thickness usinghigh-resolution ultrasonography (
      • Tanigawa T.
      • Kitamura A.
      • Yamagishi K.
      • Sakurai S.
      • Nakata A.
      • Yamashita H.
      • Sato S.
      • Ohira T.
      • Imano H.
      • Shimamoto T.T.
      • et al.
      Relationships of differential leukocyte and lymphocytesubpopulations with carotid atherosclerosis in elderly men.
      ). Finally, certain subsets of B-cells arecharacterized by increased CD1d expression (
      • Mizoguchi A.
      • Mizoguchi E.
      • Takedatsu H.
      • Blumberg R.S.
      • Bhan A.K.K.
      Chronic intestinal inflammatorycondition generates IL-10-producing regulatory B cell subset characterized byCD1d upregulation.
      ), which implies that certain B-cells could potentiallypresent lipid antigens to NKT cells, although this intriguing link toatherogenesis has not been demonstrated.
      In addition to their ability toproduce antibodies and present antigens to T-cells, it was recently demonstratedthat B-cells can regulate the immune response directly through cytokine secretionas well. Under certain conditions, B-cells are able to produce a variety ofcytokines once thought to be restricted to T-cells, including IL-1, IL-2, IL-4,IL-6, IL-10, IL-12, IL-13, IL-16, IFN-γ, lymphotoxin-α and -β,transforming growth factor-β, and TNF-α (
      • Afek A.
      • Harats D.
      • Roth A.
      • Keren G.
      • George J.
      Evidence for the involvement of T cell costimulationthrough the B-7/CD28 pathway in atherosclerotic plaques from apolipoprotein Eknockout mice.
      ). The particular cytokines produced by any givenB-cell appear to be context-dependent, influenced by both the local cytokinemilieu and any stimulatory signals (such as through the B-cell receptor or CD40)(
      • Duddy M.E.
      • Alter A.
      • Bar-Or A.
      Distinct profiles of human B cell effector cytokines: a rolein immune regulation.
      ). Distinct subsets ofcytokine-secreting B-cells have been identified recently. Effector B-cells (Be1and Be2) secrete either type 1 cytokines (IFN-γ, IL-12, andlymphotoxin-α) or type 2 cytokines (IL-2, IL-4, and IL-6) respectively(
      • Lund F.E.
      • Garvy B.A.
      • Randall T.D.
      • Harris D.P.
      Regulatory roles for cytokine-producing B cellsin infection and autoimmune disease.
      ,
      • Harris D.P.
      • Haynes L.
      • Sayles P.C.
      • Duso D.K.
      • Eaton S.M.
      • Lepak N.M.
      • Johnson L.L.
      • Swain S.L.
      • Lund F.E.E.
      Reciprocal regulation of polarized cytokine production byeffector B and T cells.
      ), analogous to the Th1 versus Th2 polarizationparadigm of T-lymphocytes. Regulatory B-cells are similar to Treg inthat they primarily produce the antiatherogenic cytokine IL-10, which cansuppress inflammation and inhibit the Th1-biased response (
      • Lund F.E.
      • Garvy B.A.
      • Randall T.D.
      • Harris D.P.
      Regulatory roles for cytokine-producing B cellsin infection and autoimmune disease.
      ). Interestingly, B-1 cells are a majorsource of B-cell-derived IL-10 (
      • O'Garra A.
      • Chang R.
      • Go N.
      • Hastings R.
      • Haughton G.
      • Howard M.
      Ly-1 B (B-1) cells arethe main source of B cell-derived interleukin 10.
      ), which may implicate this subset of B-cells inhelping to suppress the inflammatory response to OxLDL in atherogenesis. Althoughintriguing and potentially important in the pathogenesis of atherosclerosis,there is currently a paucity of studies that examine the specific role ofcytokine production by B-cells in this diseaseprocess.

      CONCLUSIONS

      Atherosclerosis is indeed acomplex inflammatory disease, and this review has focused on a number of celltypes that participate in this inflammatory response. As mentioned above, themacrophage foam cell, the fibroproliferative vascular smooth muscle cell, and thevascular endothelial cell constitute the major cell types involved in thisdisease and really should still be regarded as the “usual suspects”in atherogenesis. Despite the emerging roles that other inflammatory cells andregulatory lymphocytes may play in atherogenesis, it is important to keep in mindthat these cells are quantitatively minor components of lesions and by themselvesprobably are not sufficient for the development of atherosclerosis but ratherappear to modulate the course of the disease. That said, the roles played bythese “unusual suspects” are becoming increasingly important inunderstanding the complexity of this disease process that encompasseshemodynamics and biorheology, lipid and lipoprotein metabolism, coagulation andhemostasis, and finally innate and adaptive immunity. The immune networks at playare recognized to be increasingly complex, with multiple cellular and molecularinteractions dictating the characteristics of the inflammatory response. To date,knockout and transgenic studies in mice have proved extremely useful indelineating the atherogenicity of each of these particular cell types, affectingatherosclerosis through both general immune responses and more plaque-specificimmune responses. Looking forward, these unusual suspects may become even moreprevalent when dissecting the complex cellular interactions that occur in thecontext of atherosclerosis, and they may prove to be useful therapeutic targetsin preventing the clinical complications of this diseaseprocess.

      Acknowledgments

      The authors thank Godfrey Getz for criticalreading of the manuscript. This work was supported by CardiovascularPathophysiology and Biochemistry Training Grant HL-007237 and Medical ScientistTraining Program Grant GM-007281 to P.A.V. and National Institutes of HealthGrant HL-068661.

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