Advertisement

Galectin-1 Co-clusters CD43/CD45 on Dendritic Cells and Induces Cell Activation and Migration through Syk and Protein Kinase C Signaling*

  • Jennifer A. Fulcher
    Footnotes
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Margaret H. Chang
    Footnotes
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Shuo Wang
    Affiliations
    Department of Microbiology, Immunology, and Molecular Genetics, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Tim Almazan
    Affiliations
    Department of Microbiology, Immunology, and Molecular Genetics, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Sara T. Hashimi
    Footnotes
    Affiliations
    Department of Microbiology, Immunology, and Molecular Genetics, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Anna U. Eriksson
    Affiliations
    Department of Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Xiangshu Wen
    Affiliations
    Department of Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Mabel Pang
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Linda G. Baum
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Ram Raj Singh
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095

    Department of Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Benhur Lee
    Correspondence
    Charles E. Culpepper Medical Scholar supported by the Rockefeller Brothers Fund. To whom correspondence should be addressed: 257 BSRB, 615 Charles E. Young Dr. East, UCLA, Los Angeles, CA 90095. Tel.: 310-794-2132; Fax: 310-267-2580
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095

    Department of Microbiology, Immunology, and Molecular Genetics, Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095
    Search for articles by this author
  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grant AI060694 (to B. L. and L. G. B.), Grants AI080778 and AR056465 (to R. R. S.), Training Grants AI07126-30 (to J. A. F.), Grant HL096392 (to M. H. C.), and Grant GM08042 (to J. A. F. and M. H. C.).
    The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and supplemental text.
    1 Both authors contributed equally to this work.
    3 Supported by National Science Foundation Integrative Graduate Education and Research Traineeship Award DGE-9987641.
    2 Supported by the American College of Rheumatology Research and Education Foundation.
Open AccessPublished:July 27, 2009DOI:https://doi.org/10.1074/jbc.M109.037507
      Galectin-1 is a galactoside-binding lectin expressed in multiple tissues that has pleiotropic immunomodulatory functions. We previously showed that galectin-1 activates human monocyte-derived dendritic cells (MDDCs) and triggers a specific genetic program that up-regulates DC migration through the extracellular matrix, an integral property of mucosal DCs. Here, we identify the galectin-1 receptors on MDDCs and immediate downstream effectors of galectin-1-induced MDDC activation and migration. Galectin-1 binding to surface CD43 and CD45 on MDDCs induced an unusual unipolar co-clustering of these receptors and activates a dose-dependent calcium flux that is abrogated by lactose. Using a kinome screen and a systems biology approach, we identified Syk and protein kinase C tyrosine kinases as mediators of the DC activation effects of galectin-1. Galectin-1, but not lipopolysaccharide, stimulated Syk phosphorylation and recruitment of phosphorylated Syk to the CD43 and CD45 co-cluster on MDDCs. Inhibitors of Syk and protein kinase C signaling abrogated galectin-1-induced DC activation as monitored by interleukin-6 production; and MMP-1, -10, and -12 gene up-regulation; and enhanced migration through the extracellular matrix. The latter two are specific features of galectin-1-activated DCs. Interestingly, we also found that galectin-1 can prime DCs to respond more quickly to low dose lipopolysaccharide stimulation. Finally, we underscore the biological relevance of galectin-1-enhanced DC migration by showing that intradermal injection of galectin-1 in MRL-fas mice, which have a defect in skin DC emigration, increased the in vivo migration of dermal DCs to draining lymph nodes.
      Dendritic cells (DCs)
      The abbreviations used are: DC
      dendritic cell
      MDDC
      monocyte-derived dendritic cell
      PKC
      protein kinase C
      LPS
      lipopolysaccharide
      IL
      interleukin
      MAPK
      mitogen-activated kinase
      Erk
      extracellular signal-regulated kinase
      PTK
      protein-tyrosine kinase
      BMDC
      bone marrow-derived dendritic cells
      PBS
      phosphate-buffered saline
      DTT
      dithiothreitol
      MOPS
      4-morpholinepropanesulfonic acid
      ELISA
      enzyme-linked immunosorbent assay
      RT
      reverse transcription
      FITC
      fluorescein isothiocyanate
      PLC
      phospholipase C
      MMP
      matrix metalloproteinase
      pSyk
      phosphorylated Syk
      PI3K
      phosphatidylinositol 3-kinase.
      5The abbreviations used are: DC
      dendritic cell
      MDDC
      monocyte-derived dendritic cell
      PKC
      protein kinase C
      LPS
      lipopolysaccharide
      IL
      interleukin
      MAPK
      mitogen-activated kinase
      Erk
      extracellular signal-regulated kinase
      PTK
      protein-tyrosine kinase
      BMDC
      bone marrow-derived dendritic cells
      PBS
      phosphate-buffered saline
      DTT
      dithiothreitol
      MOPS
      4-morpholinepropanesulfonic acid
      ELISA
      enzyme-linked immunosorbent assay
      RT
      reverse transcription
      FITC
      fluorescein isothiocyanate
      PLC
      phospholipase C
      MMP
      matrix metalloproteinase
      pSyk
      phosphorylated Syk
      PI3K
      phosphatidylinositol 3-kinase.
      are critical regulators of immunity that sample and present antigen, initiate adaptive immune responses through T cell interactions, and maintain self-tolerance through T cell instruction (
      • Banchereau J.
      • Briere F.
      • Caux C.
      • Davoust J.
      • Lebecque S.
      • Liu Y.J.
      • Pulendran B.
      • Palucka K.
      ,
      • Banchereau J.
      • Steinman R.M.
      ). To effectively mount an immune response, DCs must encounter antigen and receive a signal to initiate an activation program termed “maturation.” Both exogenous and endogenous signals can initiate DC maturation. Exogenous maturation signals include Toll-like receptor ligation via pathogen components such as bacterial proteins (e.g. LPS), bacterial DNA (through CpG-containing motifs), and viral double-stranded RNA (
      • Akira S.
      • Takeda K.
      ,
      • Iwasaki A.
      • Medzhitov R.
      ). In synergy with these pathogen signals, or alone, endogenous DC activators include inflammatory cytokines, prostaglandins, and other danger signals (
      • Gallucci S.
      • Matzinger P.
      ).
      Recent work has also demonstrated that galectins, a family of endogenous β-galactoside binding lectins, can initiate DC maturation (
      • Perone M.J.
      • Larregina A.T.
      • Shufesky W.J.
      • Papworth G.D.
      • Sullivan M.L.
      • Zahorchak A.F.
      • Stolz D.B.
      • Baum L.G.
      • Watkins S.C.
      • Thomson A.W.
      • Morelli A.E.
      ,
      • Fulcher J.A.
      • Hashimi S.T.
      • Levroney E.L.
      • Pang M.
      • Gurney K.B.
      • Baum L.G.
      • Lee B.
      ,
      • Dai S.Y.
      • Nakagawa R.
      • Itoh A.
      • Murakami H.
      • Kashio Y.
      • Abe H.
      • Katoh S.
      • Kontani K.
      • Kihara M.
      • Zhang S.L.
      • Hata T.
      • Nakamura T.
      • Yamauchi A.
      • Hirashima M.
      ). The galectins have numerous known immunomodulatory activities involving T and B cells, but the role of these lectins in DC function is only beginning to be investigated. Galectin-9 matures DCs into IL-12-producing cells, which can elicit a Th1 response from T cells following co-culture (
      • Dai S.Y.
      • Nakagawa R.
      • Itoh A.
      • Murakami H.
      • Kashio Y.
      • Abe H.
      • Katoh S.
      • Kontani K.
      • Kihara M.
      • Zhang S.L.
      • Hata T.
      • Nakamura T.
      • Yamauchi A.
      • Hirashima M.
      ). On the other hand, galectin-3 influences the type of adaptive immune response initiated by DCs but does not directly affect the maturation process (
      • Breuilh L.
      • Vanhoutte F.
      • Fontaine J.
      • van Stijn C.M.
      • Tillie-Leblond I.
      • Capron M.
      • Faveeuw C.
      • Jouault T.
      • van Die I.
      • Gosset P.
      • Trottein F.
      ). We and others have shown that galectin-1 matures DCs and further enhances the migratory capacity of these cells (
      • Perone M.J.
      • Larregina A.T.
      • Shufesky W.J.
      • Papworth G.D.
      • Sullivan M.L.
      • Zahorchak A.F.
      • Stolz D.B.
      • Baum L.G.
      • Watkins S.C.
      • Thomson A.W.
      • Morelli A.E.
      ,
      • Fulcher J.A.
      • Hashimi S.T.
      • Levroney E.L.
      • Pang M.
      • Gurney K.B.
      • Baum L.G.
      • Lee B.
      ). Furthermore, galectin-1 differentially regulates gene expression in maturing DCs, as compared with LPS stimulation, indicating that galectin-1 employs a distinct maturation pathway (
      • Fulcher J.A.
      • Hashimi S.T.
      • Levroney E.L.
      • Pang M.
      • Gurney K.B.
      • Baum L.G.
      • Lee B.
      ). In the current study we identify and characterize the immediate downstream effectors that preferentially mediate the effects of galectin-1 on DC maturation.
      The downstream signaling events associated with classical DC maturation have been partially elucidated. For example, LPS induces activation of NF-κB and of MAPK pathways (particularly p38 and Erk1/2) (
      • Akira S.
      • Takeda K.
      ). However, the persistence of the maturation signal and the nature of stimulus can have disparate effects on the functional outcomes of pathways leading to DC maturation (
      • Luft T.
      • Maraskovsky E.
      • Schnurr M.
      • Knebel K.
      • Kirsch M.
      • Görner M.
      • Skoda R.
      • Ho A.D.
      • Nawroth P.
      • Bierhaus A.
      ). For example, Erk1/2 can exert both positive and negative effects on LPS-induced activation (
      • Luft T.
      • Maraskovsky E.
      • Schnurr M.
      • Knebel K.
      • Kirsch M.
      • Görner M.
      • Skoda R.
      • Ho A.D.
      • Nawroth P.
      • Bierhaus A.
      ,
      • Kikuchi K.
      • Yanagawa Y.
      • Iwabuchi K.
      • Onoé K.
      ,
      • Puig-Kröger A.
      • Relloso M.
      • Fernández-Capetillo O.
      • Zubiaga A.
      • Silva A.
      • Bernabéu C.
      • Corbí A.L.
      ) and can synergize with p38 to increase cytokine production but exert inhibitory effects on migration. This highlights the remarkable ability of DCs to integrate the extracellular environment, which dictates the variety and persistent quality of signals, into distinct outcomes.
      Less is known about immediate early activation events in DC maturation. In particular, what pathways or adaptor molecules link receptor engagement to these late activation events? Additionally, do early events differ between an endogenous stimulus (galectin-1) and exogenous stimulus (LPS), even though both stimuli result in DC maturation? Many immune cell signals employ adaptor proteins and kinases to integrate signals from different receptors into downstream events. Primarily, these upstream mediators include protein-tyrosine kinases (PTKs), such as Src family kinases. Phosphorylated PTKs in turn recruit and activate additional downstream effectors including MAPKs, small GTPases (Rac1 and Cdc42), and transcription factors (
      • Samelson L.E.
      ). The recruitment of distinct PTKs and/or adaptor proteins could be one mechanism by which DCs coordinate and regulate distinct and multiple stimuli into a specific outcome.
      Galectin-1 exists primarily as a noncovalent homodimer that recognizes the N-acetyl-lactosamine residues present on various glycoproteins and glycolipids. Thus, galectin-1 can cross-link multiple receptors on the cell surface, thereby eliciting different cell functions via formation of membrane microdomains (
      • Pace K.E.
      • Lee C.
      • Stewart P.L.
      • Baum L.G.
      ). We have shown that dimeric galectin-1 is required for DC maturation (
      • Fulcher J.A.
      • Hashimi S.T.
      • Levroney E.L.
      • Pang M.
      • Gurney K.B.
      • Baum L.G.
      • Lee B.
      ), implying that cross-linking of receptors is involved in transducing the maturation signal. Here, we identify the cognate galectin-1 receptors on MDDCs and further characterize the immediate downstream effectors that mediate the novel effects of galectin-1 on these cells. Specifically, we show that galectin-1 binds to two DC surface glycoproteins, CD43 and CD45, and induces unipolar co-clustering of these two receptors on the DC surface. Additionally, using a kinome array and a systems biology approach, we identify multiple phosphorylated signaling mediators preferentially induced by galectin-1 over LPS and implicate Syk and PKC as unique PTKs that mediate galectin-1 specific effects on DCs. Furthermore, we show that galectin-1 can prime DCs to respond more quickly to low dose LPS stimulation, suggesting a synergism between endogenous and exogenous DC activation signals that has been heretofore unappreciated. Finally, we also show that galectin-1 can enhance the in vivo migration of dermal DCs to draining lymph nodes in lupus-prone MRL-fas mice, which have a defect in skin DC emigration, underscoring the biological relevance of our results.

      DISCUSSION

      Although galectin-1 and LPS can both induce MDDC maturation, there are differences that distinguish the two stimuli. For example, galectin-1 specifically increases expression of genes related to cell motility and migration and enhances MDDC migration through the extracellular matrix (
      • Fulcher J.A.
      • Hashimi S.T.
      • Levroney E.L.
      • Pang M.
      • Gurney K.B.
      • Baum L.G.
      • Lee B.
      ).
      In the current study, we identified galectin-1 receptors on MDDCs and characterized the immediate downstream effectors that mediate the effects of galectin-1 on MDDCs. Galectin-1 bound to glycans on CD43 and CD45 and co-clustered these glycoproteins on the DC surface (Fig. 1). Galectin-1 induced a calcium flux and activated overlapping as well as distinct signaling pathways compared with LPS (FIGURE 2, FIGURE 3, FIGURE 4). Specifically, we identified Syk and PKC protein-tyrosine kinases as critical mediators of the effects of galectin-1 on MDDCs, because Syk and PKC inhibitors abrogated the effects of galectin-1 on MDDCs (Figs. 3 and 6). Galectin-1 stimulated Syk phosphorylation (Fig. 4), which then clustered with both galectin-1 receptors CD43 and CD45 on membranes of MDDCs (Fig. 5). Syk and PKC activities were also necessary for galectin-1-induced MMP gene expression and enhanced migration through Matrigel (Fig. 6). Finally, although galectin-1-induced maturation of DCs has been independently demonstrated in vivo using various murine models (
      • Perone M.J.
      • Larregina A.T.
      • Shufesky W.J.
      • Papworth G.D.
      • Sullivan M.L.
      • Zahorchak A.F.
      • Stolz D.B.
      • Baum L.G.
      • Watkins S.C.
      • Thomson A.W.
      • Morelli A.E.
      ,
      • Blois S.M.
      • Ilarregui J.M.
      • Tometten M.
      • Garcia M.
      • Orsal A.S.
      • Cordo-Russo R.
      • Toscano M.A.
      • Bianco G.A.
      • Kobelt P.
      • Handjiski B.
      • Tirado I.
      • Markert U.R.
      • Klapp B.F.
      • Poirier F.
      • Szekeres-Bartho J.
      • Rabinovich G.A.
      • Arck P.C.
      ), we now also provide in vivo evidence for a distinguishing feature of galectin-1-activated DCs: enhanced migration through the extracellular matrix. Fig. 8 shows that a single intradermal injection of recombinant galectin-1 could partially rectify the defect in skin DC emigration seen in lupus-prone MRL-fas mice and induced migration of various types of skin DCs into draining lymph nodes.
      Although we have shown that galectin-1 clearly bound and clustered CD43 and CD45 on MDDCs, we acknowledge that galectin-1 may have additional counter-receptors on the DC plasma membrane, and the role of other receptors in galectin-1-mediated signaling on MDDCs remains to be determined. For example, Syk has essential roles in integrin signaling (
      • Mócsai A.
      • Zhou M.
      • Meng F.
      • Tybulewicz V.L.
      • Lowell C.A.
      ,
      • Obergfell A.
      • Eto K.
      • Mocsai A.
      • Buensuceso C.
      • Moores S.L.
      • Brugge J.S.
      • Lowell C.A.
      • Shattil S.J.
      ,
      • Vines C.M.
      • Potter J.W.
      • Xu Y.
      • Geahlen R.L.
      • Costello P.S.
      • Tybulewicz V.L.
      • Lowell C.A.
      • Chang P.W.
      • Gresham H.D.
      • Willman C.L.
      ), and integrin β1 is another known galectin-1 receptor (
      • Elola M.T.
      • Chiesa M.E.
      • Alberti A.F.
      • Mordoh J.
      • Fink N.E.
      ). Further, data from the kinome array shows that galectin-1 affected multiple phosphorylated proteins that have known roles in integrin signaling, and integrin β1 itself was also phosphorylated (Table 1). Galectin-1-mediated DC maturation likely involves coordinated binding of multiple receptors and utilization of unique upstream mediators to link common signaling pathways. Thus, future studies will test the contributory role of each galectin-1 receptor to fully delineate the complex mechanism of galectin-1 signaling in DCs.
      The “danger signal model” proposes that immune responses can also be driven by self-signals that signal danger in the absence of a pathogen, i.e. by signals sent from dying or damaged cells (
      • Matzinger P.
      ,
      • Matzinger P.
      ,
      • Matzinger P.
      ). Because galectin-1 is present at high concentrations (up to 48 mg/kg) in extracellular matrix and in multiple anatomic sites (
      • Ahmed H.
      • Fink N.E.
      • Pohl J.
      • Vasta G.R.
      ) and its secretion by endothelium and immune cells is increased during inflammation (
      • Baum L.G.
      • Seilhamer J.J.
      • Pang M.
      • Levine W.B.
      • Beynon D.
      • Berliner J.A.
      ) or can be concentrated in stromal sites to potentiate its activity (
      • He J.
      • Baum L.G.
      ), galectin-1 may function as an endogenous inducible danger signal (
      • Gallucci S.
      • Lolkema M.
      • Matzinger P.
      ) that enhances the inflammatory response to exogenous pathogen signals. Indeed, we found that priming the DCs with pre-exposure to galectin-1 enhances the inflammatory response time of DCs to suboptimal LPS stimulus (Fig. 7C). Thus, endogenous cues, such as galectin-1, which can be highly up-regulated in inflammatory situations, can potentially synergize with pathogen-derived signals (like LPS) and activate dendritic cells in a manner that has not been heretofore appreciated. Our results also suggest that, at some level, LPS and galectin-1 signaling pathways converge. Thus, although our data show that the Syk and PKC pathways can preferentially mediate galectin-1 effects on DCs, we do not imply that LPS does not activate these pathways at all. Indeed, LPS is known to activate the Syk pathway in neutrophils (
      • Arndt P.G.
      • Suzuki N.
      • Avdi N.J.
      • Malcolm K.C.
      • Worthen G.S.
      ), and our inhibitor, time course, and phosphorylation studies indicate that LPS may simply activate the Syk pathway in DCs in a distinct but overlapping manner.
      Our data also show that the role of galectin-1 as an endogenous activator of DCs can induce functionally different responses from a classic exogenous stimulus like LPS. Galectin-1 is well known as a fine-tuner of immune responses (
      • Rabinovich G.A.
      • Rubinstein N.
      • Toscano M.A.
      ,
      • Rabinovich G.A.
      • Toscano M.A.
      • Ilarregui J.M.
      • Rubinstein N.
      ,
      • Rabinovich G.A.
      • Baum L.G.
      • Tinari N.
      • Paganelli R.
      • Natoli C.
      • Liu F.T.
      • Iacobelli S.
      ), and a multitude of studies have shown that exogenously administered galectin-1 can dampen a host of autoimmune and inflammatory responses in animal models (
      • Camby I.
      • Le Mercier M.
      • Lefranc F.
      • Kiss R.
      ). However, the vast majority of studies have focused on the ability of galectin-1 to modulate T cell responses. Galectin-1 clearly matures dendritic cells, as has been independently demonstrated by Morelli and co-workers (
      • Perone M.J.
      • Larregina A.T.
      • Shufesky W.J.
      • Papworth G.D.
      • Sullivan M.L.
      • Zahorchak A.F.
      • Stolz D.B.
      • Baum L.G.
      • Watkins S.C.
      • Thomson A.W.
      • Morelli A.E.
      ), but even this work focused on the ability of transgenic galectin-1-matured DCs to modulate T cell responses in vivo. Here, we showed that our in vitro observation that galectin-1-activated DCs have enhanced migratory capacity through the extracellular matrix is also seen in vivo. Indeed, galectin-1 rescued the defect in skin DC emigration seen in lupus-prone MRL-fas mice. This raises the question of whether galectin-1 plays a role in the basal constitutive migration of tissue DCs from the periphery to central lymphoid organs, an event that is thought to be necessary for the maintenance of peripheral tolerance (
      • Steinman R.M.
      • Hawiger D.
      • Nussenzweig M.C.
      ,
      • Lutz M.B.
      • Schuler G.
      ,
      • Morelli A.E.
      • Thomson A.W.
      ). Our results suggest that despite the unquestionable role that galectin-1 plays in T cell modulation, a more holistic view of how galectin-1 also affects DCs, a cell that is the nexus of innate and adaptive immunity, is called for.

      Acknowledgments

      We gratefully acknowledge the support of all members of the Lee laboratory, particularly Y. Wang and H. Nassanian, for technical assistance. We also acknowledge the support of D. Anisman-Posner from the UCLA AIDS Institute Virology Core (UCLA AIDS Institute AI26897) and T. Phung at the UCLA Flow Cytometry Core (UCLA Center for AIDS Research CA-16042).

      REFERENCES

        • Banchereau J.
        • Briere F.
        • Caux C.
        • Davoust J.
        • Lebecque S.
        • Liu Y.J.
        • Pulendran B.
        • Palucka K.
        Annu Rev. Immunol. 2000; 18: 767-811
        • Banchereau J.
        • Steinman R.M.
        Nature. 1998; 392: 245-252
        • Akira S.
        • Takeda K.
        Nat. Rev. Immunol. 2004; 4: 499-511
        • Iwasaki A.
        • Medzhitov R.
        Nat. Immunol. 2004; 5: 987-995
        • Gallucci S.
        • Matzinger P.
        Curr. Opin. Immunol. 2001; 13: 114-119
        • Perone M.J.
        • Larregina A.T.
        • Shufesky W.J.
        • Papworth G.D.
        • Sullivan M.L.
        • Zahorchak A.F.
        • Stolz D.B.
        • Baum L.G.
        • Watkins S.C.
        • Thomson A.W.
        • Morelli A.E.
        J. Immunol. 2006; 176: 7207-7220
        • Fulcher J.A.
        • Hashimi S.T.
        • Levroney E.L.
        • Pang M.
        • Gurney K.B.
        • Baum L.G.
        • Lee B.
        J. Immunol. 2006; 177: 216-226
        • Dai S.Y.
        • Nakagawa R.
        • Itoh A.
        • Murakami H.
        • Kashio Y.
        • Abe H.
        • Katoh S.
        • Kontani K.
        • Kihara M.
        • Zhang S.L.
        • Hata T.
        • Nakamura T.
        • Yamauchi A.
        • Hirashima M.
        J. Immunol. 2005; 175: 2974-2981
        • Breuilh L.
        • Vanhoutte F.
        • Fontaine J.
        • van Stijn C.M.
        • Tillie-Leblond I.
        • Capron M.
        • Faveeuw C.
        • Jouault T.
        • van Die I.
        • Gosset P.
        • Trottein F.
        Infect. Immun. 2007; 75: 5148-5157
        • Luft T.
        • Maraskovsky E.
        • Schnurr M.
        • Knebel K.
        • Kirsch M.
        • Görner M.
        • Skoda R.
        • Ho A.D.
        • Nawroth P.
        • Bierhaus A.
        Blood. 2004; 104: 1066-1074
        • Kikuchi K.
        • Yanagawa Y.
        • Iwabuchi K.
        • Onoé K.
        Immunol. Lett. 2003; 89: 149-154
        • Puig-Kröger A.
        • Relloso M.
        • Fernández-Capetillo O.
        • Zubiaga A.
        • Silva A.
        • Bernabéu C.
        • Corbí A.L.
        Blood. 2001; 98: 2175-2182
        • Samelson L.E.
        Annu Rev. Immunol. 2002; 20: 371-394
        • Pace K.E.
        • Lee C.
        • Stewart P.L.
        • Baum L.G.
        J. Immunol. 1999; 163: 3801-3811
        • Lutz M.B.
        • Kukutsch N.
        • Ogilvie A.L.
        • Rössner S.
        • Koch F.
        • Romani N.
        • Schuler G.
        J. Immunol. Methods. 1999; 223: 77-92
        • Pace K.E.
        • Hahn H.P.
        • Baum L.G.
        Methods Enzymol. 2003; 363: 499-518
        • Shimomura H.
        • Matsuura M.
        • Saito S.
        • Hirai Y.
        • Isshiki Y.
        • Kawahara K.
        Infect. Immun. 2003; 71: 5225-5230
        • Elola M.T.
        • Chiesa M.E.
        • Alberti A.F.
        • Mordoh J.
        • Fink N.E.
        J. Biomed. Sci. 2005; 12: 13-29
        • Cho M.
        • Cummings R.D.
        J. Biol. Chem. 1995; 270: 5198-5206
        • Corinti S.
        • Fanales-Belasio E.
        • Albanesi C.
        • Cavani A.
        • Angelisova P.
        • Girolomoni G.
        J. Immunol. 1999; 162: 6331-6336
        • Miura Y.
        • Mizutani C.
        • Nishihara T.
        • Hishita T.
        • Yanagi S.
        • Tohyama Y.
        • Ichiyama S.
        • Yamamura H.
        • Uchiyama T.
        • Tohyama K.
        Biochem. Biophys. Res. Commun. 2001; 288: 80-86
        • Wong R.C.
        • Remold-O'Donnell E.
        • Vercelli D.
        • Sancho J.
        • Terhorst C.
        • Rosen F.
        • Geha R.
        • Chatila T.
        J. Immunol. 1990; 144: 1455-1460
        • Silverman L.B.
        • Wong R.C.
        • Remold-O'Donnell E.
        • Vercelli D.
        • Sancho J.
        • Terhorst C.
        • Rosen F.
        • Geha R.
        • Chatila T.
        J. Immunol. 1989; 142: 4194-4200
        • Pedraza-Alva G.
        • Mérida L.B.
        • Burakoff S.J.
        • Rosenstein Y.
        J. Biol. Chem. 1996; 271: 27564-27568
        • Alvarado M.
        • Klassen C.
        • Cerny J.
        • Horejsí V.
        • Schmidt R.E.
        Eur. J. Immunol. 1995; 25: 1051-1055
        • Spertini F.
        • Perret-Menoud V.
        • Barbier N.
        • Chatila T.
        • Barbey C.
        • Corthesy B.
        Immunology. 2004; 113: 441-452
        • Park S.J.
        • Nakagawa T.
        • Kitamura H.
        • Atsumi T.
        • Kamon H.
        • Sawa S.
        • Kamimura D.
        • Ueda N.
        • Iwakura Y.
        • Ishihara K.
        • Murakami M.
        • Hirano T.
        J. Immunol. 2004; 173: 3844-3854
        • Jonuleit H.
        • Kühn U.
        • Müller G.
        • Steinbrink K.
        • Paragnik L.
        • Schmitt E.
        • Knop J.
        • Enk A.H.
        Eur. J. Immunol. 1997; 27: 3135-3142
        • Geisel J.
        • Kahl F.
        • Müller M.
        • Wagner H.
        • Kirschning C.J.
        • Autenrieth I.B.
        • Frick J.S.
        J. Immunol. 2007; 179: 5811-5818
        • Baum L.G.
        • Seilhamer J.J.
        • Pang M.
        • Levine W.B.
        • Beynon D.
        • Berliner J.A.
        Glycoconj. J. 1995; 12: 63-68
        • Ahmed H.
        • Fink N.E.
        • Pohl J.
        • Vasta G.R.
        J. Biochem. 1996; 120: 1007-1019
        • Eriksson A.U.
        • Singh R.R.
        J. Immunol. 2008; 181: 7468-7472
        • Dupasquier M.
        • Stoitzner P.
        • van Oudenaren A.
        • Romani N.
        • Leenen P.J.
        J. Invest. Dermatol. 2004; 123: 876-879
        • Blois S.M.
        • Ilarregui J.M.
        • Tometten M.
        • Garcia M.
        • Orsal A.S.
        • Cordo-Russo R.
        • Toscano M.A.
        • Bianco G.A.
        • Kobelt P.
        • Handjiski B.
        • Tirado I.
        • Markert U.R.
        • Klapp B.F.
        • Poirier F.
        • Szekeres-Bartho J.
        • Rabinovich G.A.
        • Arck P.C.
        Nat. Med. 2007; 13: 1450-1457
        • Mócsai A.
        • Zhou M.
        • Meng F.
        • Tybulewicz V.L.
        • Lowell C.A.
        Immunity. 2002; 16: 547-558
        • Obergfell A.
        • Eto K.
        • Mocsai A.
        • Buensuceso C.
        • Moores S.L.
        • Brugge J.S.
        • Lowell C.A.
        • Shattil S.J.
        J. Cell Biol. 2002; 157: 265-275
        • Vines C.M.
        • Potter J.W.
        • Xu Y.
        • Geahlen R.L.
        • Costello P.S.
        • Tybulewicz V.L.
        • Lowell C.A.
        • Chang P.W.
        • Gresham H.D.
        • Willman C.L.
        Immunity. 2001; 15: 507-519
        • Matzinger P.
        Science. 2002; 296: 301-305
        • Matzinger P.
        Semin Immunol. 1998; 10: 399-415
        • Matzinger P.
        Annu. Rev. Immunol. 1994; 12: 991-1045
        • He J.
        • Baum L.G.
        J. Biol. Chem. 2004; 279: 4705-4712
        • Gallucci S.
        • Lolkema M.
        • Matzinger P.
        Nat. Med. 1999; 5: 1249-1255
        • Arndt P.G.
        • Suzuki N.
        • Avdi N.J.
        • Malcolm K.C.
        • Worthen G.S.
        J. Biol. Chem. 2004; 279: 10883-10891
        • Rabinovich G.A.
        • Rubinstein N.
        • Toscano M.A.
        Biochim. Biophys. Acta. 2002; 1572: 274-284
        • Rabinovich G.A.
        • Toscano M.A.
        • Ilarregui J.M.
        • Rubinstein N.
        Glycoconj. J. 2004; 19: 565-573
        • Rabinovich G.A.
        • Baum L.G.
        • Tinari N.
        • Paganelli R.
        • Natoli C.
        • Liu F.T.
        • Iacobelli S.
        Trends Immunol. 2002; 23: 313-320
        • Camby I.
        • Le Mercier M.
        • Lefranc F.
        • Kiss R.
        Glycobiology. 2006; 16: 137R-157R
        • Steinman R.M.
        • Hawiger D.
        • Nussenzweig M.C.
        Annu. Rev. Immunol. 2003; 21: 685-711
        • Lutz M.B.
        • Schuler G.
        Trends Immunol. 2002; 23: 445-449
        • Morelli A.E.
        • Thomson A.W.
        Nat. Rev. Immunol. 2007; 7: 610-621