Review Article | Published:

Turning 'sweet' on immunity: galectin–glycan interactions in immune tolerance and inflammation

Nature Reviews Immunology volume 9, pages 338352 (2009) | Download Citation

This article has been updated

Abstract

The function of deciphering the biological information encoded by the glycome, which is the entire repertoire of complex sugar structures expressed by cells and tissues, is assigned in part to endogenous glycan-binding proteins or lectins. Galectins, a family of animal lectins that bind N-acetyllactosamine-containing glycans, have many roles in diverse immune cell processes, including those relevant to pathogen recognition, shaping the course of adaptive immune responses and fine-tuning the inflammatory response. How do galectins translate glycan-encoded information into tolerogenic or inflammatory cell programmes? An improved understanding of the mechanisms underlying these functions will provide further opportunities for developing new therapies based on the immunoregulatory properties of this multifaceted protein family.

Key points

  • Galectins are evolutionarily conserved glycan-binding proteins with pleiotropic roles in innate and adaptive immune responses. Extracellularly, galectins can bind multiple glycosylated binding partners and translate glycan-encoded information into immune cell homeostatic programmes.

  • Galectin–glycoprotein interactions form a multivalent 'lattice' that controls glycoprotein clustering and endocytosis to regulate receptor signalling and activation.

  • Several members of the galectin family trigger intracellular signals that lead to the regulation of T cell survival. This process is controlled by the glycosylation pattern of cell surface glycoproteins, which can change markedly during activation and differentiation of immune cells.

  • Galectin 1 and galectin 10 are over-represented in CD4+CD25+ regulatory T (TReg) cells and contribute to their immunosuppressive activity. In addition, galectins contribute to shaping the B cell compartment during B cell development and differentiation.

  • Emerging evidence in knockout mice indicates crucial roles for endogenous galectins in modulating chronic inflammation, autoimmunity and allergy. In addition, galectins can function as soluble mediators that are used by tumour cells to evade immune responses.

  • The essential roles of galectin–glycan interactions in immune tolerance and homeostasis make them attractive therapeutic targets for limiting autoimmune inflammation, preventing allograft rejection and potentiating antitumour responses.

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Change history

  • 17 April 2009

    In the version of this article initially published online, the first reference in Table 2, page 10, was incorrect. In addition, in page 9, the sentence "impairs the ability of T cells to stimulate macrophages" was incorrect and should be "impairs the ability of macrophages to stimulate T cells". These errors have been corrected for the print, HTML and PDF versions of the article.

References

  1. 1.

    & Mammalian glycosylation in immunity. Nature Rev. Immunol. 8, 874–887 (2008). This review provides a comprehensive analysis of the relevance of glycosylation in innate and adaptive immune responses.

  2. 2.

    & Protein–glycan interactions in the control of innate and adaptive immune responses. Nature Immunol. 9, 593–601 (2008).

  3. 3.

    & in Essentials of Glycobiology Second Edition (eds Varki, A. et al.) 474–784 (Cold Spring Harbor Laboratory Press, New York, 2008). This chapter provides an updated overview of biochemical, structural and biological features of different members of the galectin family.

  4. 4.

    , , & Functions of cell surface galectin–glycoprotein lattices. Curr. Opin. Struct. Biol. 17, 513–520 (2007).

  5. 5.

    , & Galectins: structure, function and therapeutic potential. Expert Rev. Mol. Med. 10, e17 (2008).

  6. 6.

    , & Clusters, bundles, arrays and lattices: novel mechanisms for lectin–saccharide-mediated cellular interactions. Curr. Opin. Struct. Biol. 12, 616–623 (2002). This review article discusses the potential of lectins and their saccharide ligands to form various types of lattice and the functional relevance of these ordered arrays in cell communication, trafficking and survival.

  7. 7.

    et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature Immunol. 6, 1245–1252 (2005).

  8. 8.

    et al. Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood 110, 1550–1558 (2007). This article identifies an essential contribution of intracellular galectin 10 to the suppressive activity of CD4+CD25+ TReg cells.

  9. 9.

    et al. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim. Biophys. Acta 1572, 232–254 (2002).

  10. 10.

    et al. Galectin-1, -2, and -3 exhibit differential recognition of sialylated glycans and blood group antigens. J. Biol. Chem. 283, 10109–10123 (2008). References 9 and 10 provide detailed information on the fine specificities of individual galectins for particular glycan structures and the potential relevance of these variations in determining functional divergences.

  11. 11.

    et al. Complex N-glycans are the major ligands for galectin-1, -3, and -8 on Chinese hamster ovary cells. Glycobiology 16, 305–317 (2006).

  12. 12.

    & Galectins as immunoregulators during infectious processes: from microbial invasion to the resolution of the disease. Parasite Immunol. 27, 103–114 (2005).

  13. 13.

    Role of galectins in infection. Nature Rev. Microbiol. (in the press)

  14. 14.

    , & Galectin-3 interacts with naive and primed neutrophils, inducing innate immune responses. J. Leukoc. Biol. 78, 1127–1135 (2005).

  15. 15.

    , , , & Evidence of a role for galectin-1 in acute inflammation. Eur. J. Immunol. 30, 1331–1338 (2000).

  16. 16.

    , , & What does the future hold for cell-based tolerogenic therapy? Nature Rev. Immunol. 7, 650–654 (2007).

  17. 17.

    , & Siglecs and their roles in the immune system. Nature Rev. Immunol. 7, 255–266 (2007).

  18. 18.

    et al. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109, 2058–2065 (2007). This article shows an essential contribution of galectin 1 to the suppressive activity of CD4+CD25+ TReg cells.

  19. 19.

    T-cell activation through immunological synapses and kinapses. Immunol. Rev. 221, 77–89 (2008).

  20. 20.

    , , & Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409, 733–739 (2001). This study defines the crucial function of N-glycan branching and galectin–glycan lattices in T cell clustering, signalling and activation.

  21. 21.

    et al. N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J. Immunol. 173, 7200–7208 (2004).

  22. 22.

    et al. Control of T cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J. Biol. Chem. 282, 20027–20035 (2007).

  23. 23.

    , & Lateral compartmentalization of T cell receptor versus CD45 by galectin–N-glycan binding and microfilaments coordinate basal and activation signaling. J. Biol. Chem. 282, 35361–35372 (2007).

  24. 24.

    , , , & Galectin-1 induces partial TCRζ-chain phosphorylation and antagonizes processive TCR signal transduction. J. Immunol. 165, 3722–3729 (2000).

  25. 25.

    et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123–134 (2007).

  26. 26.

    et al. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity 28, 414–424 (2008). This study shows the impact of galectin–glycan interactions in the regulation of tumour-induced T cell anergy.

  27. 27.

    et al. Endogenous galectin-1 enforces class I-restricted TCR functional fate decisions in thymocytes. Blood 112, 120–130 (2008). This study identifies an important role for galectin 1 in T cell signalling during negative and positive selection in the thymus.

  28. 28.

    , , & Apoptosis of T cells mediated by galectin-1. Nature 378, 736–739 (1995). This study shows for the first time the ability of galectin 1 to induce T cell apoptosis.

  29. 29.

    et al. β-galactoside-binding protein secreted by activated T cells inhibits antigen-induced proliferation of T cells. Eur. J. Immunol. 28, 2311–2319 (1998).

  30. 30.

    et al. Induction of allogenic T-cell hyporesponsiveness by galectin-1-mediated apoptotic and non-apoptotic mechanisms. Cell Death Differ. 9, 661–670 (2002).

  31. 31.

    et al. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J. Immunol. 176, 778–789 (2006).

  32. 32.

    et al. Human galectin-2: novel inducer of T cell apoptosis with distinct profile of caspase activation. J. Immunol. 173, 3825–3837 (2004).

  33. 33.

    et al. Galectin-8 induces apoptosis in the CD4highCD8high thymocyte subpopulation. Glycobiology 17, 1404–1412 (2007).

  34. 34.

    et al. Galectin-4 controls intestinal inflammation by selective regulation of peripheral and mucosal T cell apoptosis and cell cycle. PLoS ONE 3, e2629 (2008).

  35. 35.

    , , & Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J. Biol. Chem. 283, 12248–12258 (2008).

  36. 36.

    et al. CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. Cancer Res. 63, 8302–8311 (2003).

  37. 37.

    et al. Characterization of galectin-9-induced death of Jurkat T cells. J. Biochem. 141, 157–172 (2007).

  38. 38.

    et al. Galectin-1 induced activation of the apoptotic death-receptor pathway in human Jurkat T lymphocytes. Histochem. Cell. Biol. 129, 599–609 (2008).

  39. 39.

    , , & Restricted receptor segregation into membrane microdomains occurs on human T cells during apoptosis induced by galectin-1. J. Immunol. 163, 3801–3811 (1999).

  40. 40.

    , , & The ST6Gal I sialyltransferase selectively modifies N-glycans on CD45 to negatively regulate galectin-1-induced CD45 clustering, phosphatase modulation, and T cell death. J. Biol. Chem. 278, 7469–7475 (2003).

  41. 41.

    et al. CD45 modulates galectin-1-induced T cell death: regulation by expression of core 2 O-glycans. J. Immunol. 167, 5697–5707 (2001).

  42. 42.

    et al. Galectin-1 binds different CD43 glycoforms to cluster CD43 and regulate T cell death. J. Immunol. 177, 5328–5336 (2006).

  43. 43.

    et al. Differential glycosylation of TH1, TH2 and TH17 effector cells selectively regulates susceptibility to cell death. Nature Immunol. 8, 825–834 (2007).

  44. 44.

    et al. CD4+CD7 leukemic T cells from patients with Sezary syndrome are protected from galectin-1-triggered T cell death. Leukemia 16, 840–845 (2002).

  45. 45.

    et al. Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death. Blood 108, 2399–2406 (2006).

  46. 46.

    , , , & Galectin-1 functions as a Th2 cytokine that selectively induces Th1 apoptosis and promotes Th2 function. Eur. J. Immunol. 38, 3015–3027 (2008).

  47. 47.

    et al. Molecular mechanisms implicated in galectin-1-induced apoptosis: activation of the AP-1 transcription factor and downregulation of Bcl-2. Cell Death Differ. 7, 747–753 (2000).

  48. 48.

    et al. Acid sphingomyelinase-mediated release of ceramide is essential to trigger the mitochondrial pathway of apoptosis by galectin-1. Cell Signal. 18, 1887–1896 (2006).

  49. 49.

    et al. Galectin-1 sensitizes resting human T lymphocytes to Fas (CD95)-mediated cell death via mitochondrial hyperpolarization, budding, and fission. J. Biol. Chem. 280, 6969–6985 (2005).

  50. 50.

    et al. Galectin-1 induces nuclear translocation of endonuclease G in caspase- and cytochrome c-independent T cell death. Cell Death Differ. 11, 1277–1286 (2004).

  51. 51.

    , , & Galectin-1 supports survival of naive T cells without promoting cell proliferation. Eur. J. Immunol. 35, 86–97 (2005).

  52. 52.

    et al. Differential roles of galectin-1 and galectin-3 in regulating leukocyte viability and cytokine secretion. J. Immunol. 180, 3091–3102 (2008).

  53. 53.

    , , , & The thiol redox state of lymphoid organs is modified by immunization: role of different immune cell populations. Eur. J. Immunol. 38, 2419–2425 (2008).

  54. 54.

    et al. Ligand reduces galectin-1 sensitivity to oxidative inactivation by enhancing dimer formation. J. Biol. Chem. 284, 4989–4999 (2009).

  55. 55.

    , & Expression of galectin-3 modulates T-cell growth and apoptosis. Proc. Natl Acad. Sci. USA 93, 6737–6742 (1996). This study identifies the anti-apoptotic function of intracellular galectin 3.

  56. 56.

    et al. Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis. J. Immunol. 182, 1167–1173 (2009).

  57. 57.

    , & Galectin-3 gene inactivation reduces atherosclerotic lesions and adventitial inflammation in ApoE-deficient mice. Am. J. Pathol. 172, 247–255 (2008).

  58. 58.

    et al. Critical role for galectin-3 in airway inflammation and bronchial hyperresponsiveness in a murine model of asthma. Am. J. Pathol. 165, 2045–2053 (2004).

  59. 59.

    et al. Activation of Tim-3–galectin-9 pathway improves survival of fully allogeneic skin grafts. Transpl. Immunol. 19, 12–19 (2008).

  60. 60.

    et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin. Immunol. 127, 78–88 (2008).

  61. 61.

    et al. Galectin-2 induces apoptosis of lamina propria T lymphocytes and ameliorates acute and chronic experimental colitis in mice. J. Mol. Med. 86, 1395–1406 (2008).

  62. 62.

    et al. Induced reactivity of intestinal CD4+ T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation. Immunity 20, 681–693 (2004).

  63. 63.

    et al. Altered expression of galectin-3 induces cortical thymocyte depletion and premature exit of immature thymocytes during Trypanosoma cruzi infection. Am. J. Pathol. 170, 546–556 (2007).

  64. 64.

    et al. A pivotal role for galectin-1 in fetomaternal tolerance. Nature Med. 13, 1450–1457 (2007).

  65. 65.

    et al. Amelioration of graft versus host disease by galectin-1. Clin. Immunol. 109, 295–307 (2003).

  66. 66.

    et al. Dendritic cells expressing transgenic galectin-1 delay onset of autoimmune diabetes in mice. J. Immunol. 177, 5278–5289 (2006).

  67. 67.

    et al. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J. Exp. Med. 190, 385–398 (1999).

  68. 68.

    et al. Galectin-1 suppresses experimental colitis in mice. Gastroenterology 124, 1381–1394 (2003).

  69. 69.

    et al. Galectin-1 suppresses autoimmune retinal disease by promoting concomitant Th2- and T regulatory-mediated anti-inflammatory responses. J. Immunol. 176, 6323–6332 (2006).

  70. 70.

    et al. Specific inhibition of T-cell adhesion to extracellular matrix and proinflammatory cytokine secretion by human recombinant galectin-1. Immunology 97, 100–106 (1999).

  71. 71.

    et al. Galectin-1 mediated suppression of Epstein–Barr virus specific T-cell immunity in classic Hodgkin lymphoma. Blood 110, 1326–1329 (2007).

  72. 72.

    et al. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc. Natl Acad. Sci. USA 104, 13134–13139 (2007).

  73. 73.

    et al. Strongly enhanced IL-10 production using stable galectin-1 homodimers. Mol. Immunol. 44, 506–513 (2007).

  74. 74.

    et al. Gene therapy with galectin-3 inhibits bronchial obstruction and inflammation in antigen-challenged rats through interleukin-5 gene downregulation. Am. J. Respir. Crit. Care. Med. 166, 732–737 (2002).

  75. 75.

    et al. Toxoplasma gondii infection reveals a novel regulatory role for galectin-3 in the interface of innate and adaptive immunity. Am. J. Pathol. 168, 1910–1920 (2006).

  76. 76.

    et al. Galectin-3 modulates immune and inflammatory responses during helminthic infection: impact of galectin-3 deficiency on the functions of dendritic cells. Infect. Immun. 75, 5148–5157 (2007).

  77. 77.

    et al. Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis. J. Immunol. 182, 4036–4045 (2009).

  78. 78.

    , , , & Galectin-1 is a stromal cell ligand of the pre-B cell receptor (BCR) implicated in synapse formation between pre-B and stromal cells and in pre-BCR triggering. Proc. Natl Acad. Sci. USA 99, 13014–13019 (2002). This study describes the relevance of galectin 1–glycan interactions in pre-B cell–stromal cell synapse formation and pre-BCR signalling during B cell development.

  79. 79.

    , , & Clustering of pre-B cell integrins induces galectin-1-dependent pre-B cell receptor relocalization and activation. J. Immunol. 177, 796–803 (2006).

  80. 80.

    et al. Galectin-1 promotes immunoglobulin production during plasma cell differentiation. J. Immunol. 181, 4570–4579 (2008).

  81. 81.

    et al. Galectin-3 mediates IL-4-induced survival and differentiation of B cells: functional cross-talk and implications during Trypanosoma cruzi infection. J. Immunol. 172, 493–502 (2004).

  82. 82.

    et al. Multifunctional regulators of cell growth are differentially expressed in anergic murine B cells. Mol. Immunol. 44, 1274–1285 (2007).

  83. 83.

    , , & Regulated expression of galectin-1 during B-cell activation and implications for T-cell apoptosis. J. Leukoc. Biol. 70, 73–79 (2001).

  84. 84.

    et al. T cell leukemia/lymphoma 1 and galectin-1 regulate survival/cell death pathways in human naive and IgM+ memory B cells through altering balances in Bcl-2 family of proteins. J. Immunol. 182, 1490–1499 (2009).

  85. 85.

    , & Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).

  86. 86.

    et al. Dendritic cell maturation results in pronounced changes in glycan expression affecting recognition by siglecs and galectins. J. Immunol. 179, 8216–8224 (2007).

  87. 87.

    et al. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306, 120–124 (2004).

  88. 88.

    et al. Polylactosamine on glycoproteins influences basal levels of lymphocyte and macrophage activation. Proc. Natl Acad. Sci. USA 104, 15829–15834 (2007).

  89. 89.

    et al. Galectin-9 induces maturation of human monocyte-derived dendritic cells. J. Immunol. 175, 2974–2981 (2005).

  90. 90.

    et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318, 1141–1143 (2007). This article describes the dual role of galectin 9–TIM3 interactions in initiating adaptive immune responses and limiting TH1 cell-mediated autoimmune inflammation.

  91. 91.

    et al. Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9–Tim-3 interactions. J. Immunol. 181, 7660–7669 (2008).

  92. 92.

    et al. Galectin-1-matured human monocyte-derived dendritic cells have enhanced migration through extracellular matrix. J. Immunol. 177, 216–226 (2006).

  93. 93.

    et al. Endogenous galectin-3 is localized in membrane lipid rafts and regulates migration of dendritic cells. J. Invest. Dermatol. 129, 573–583 (2009).

  94. 94.

    , , , & Opposite effects of galectin-1 on alternative metabolic pathways of L-arginine in resident, inflammatory, and activated macrophages. Glycobiology 13, 119–128 (2003).

  95. 95.

    et al. A novel function for galectin-1 at the crossroad of innate and adaptive immunity: galectin-1 regulates monocyte/macrophage physiology through a nonapoptotic ERK-dependent pathway. J. Immunol. 178, 436–445 (2007).

  96. 96.

    et al. Regulation of alternative macrophage activation by galectin-3. J. Immunol. 180, 2650–2658 (2008).

  97. 97.

    , , , & Regulated expression and effect of galectin-1 on Trypanosoma cruzi-infected macrophages: modulation of microbicidal activity and survival. Infect. Immun. 69, 6804–6812 (2001).

  98. 98.

    , & Prevention and therapy with electrolectin of experimental autoimmune myasthenia gravis in rabbits. Eur. J. Immunol. 13, 500–507 (1983).

  99. 99.

    et al. Recombinant human β-galactoside binding lectin suppresses clinical and histological signs of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 28, 177–184 (1990). References 97 and 98 are early studies demonstrating the anti-inflammatory effects of galectins when injected in vivo in animal models.

  100. 100.

    et al. Galectin-1 exerts immunomodulatory and protective effects on concanavalin A-induced hepatitis in mice. Hepatology 31, 399–406 (2000).

  101. 101.

    et al. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int. 58, 1941–1952 (2000).

  102. 102.

    et al. Suppression of autoimmune diabetes by soluble galectin-1. J. Immunol. 182, 2641–2653 (2009).

  103. 103.

    & Does our current understanding of the molecular basis of immune tolerance predict new therapies for autoimmune disease? Nature Clin. Pract. Rheumatol. 2, 491–499 (2006).

  104. 104.

    & Endothelial cell expression of galectin-1 induced by prostate cancer cells inhibits T-cell transendothelial migration. Lab. Invest. 86, 578–590 (2006).

  105. 105.

    , , & Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. FASEB J. 22, 682–690 (2008).

  106. 106.

    et al. T cell apoptosis at the maternal-fetal interface in early human pregnancy, involvement of galectin-1. Proc. Natl Acad. Sci. USA 105, 18472–18477 (2008).

  107. 107.

    et al. N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. J. Biol. Chem. 282, 33725–33734 (2007).

  108. 108.

    et al. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis. Rheum. 48, 2788–2795 (2003).

  109. 109.

    et al. The involvement of CD44 and its novel ligand galectin-8 in apoptotic regulation of autoimmune inflammation. J. Immunol. 179, 1225–1235 (2007).

  110. 110.

    et al. Expression of galectins-1 and -3 correlates with defective mononuclear cell apoptosis in patients with juvenile idiopathic arthritis. J. Rheumatol. 28, 1914–1922 (2001).

  111. 111.

    et al. Galectin-3 is an amplifier of inflammation in atherosclerotic plaque progression through macrophage activation and monocyte chemoattraction. Arterioscler. Thromb. Vasc. Biol. 28, 433–440 (2008).

  112. 112.

    et al. Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-α secretion in vitro. Nature 429, 72–75 (2004).

  113. 113.

    et al. Identification of autoantibodies associated with systemic lupus erythematosus. Biochem. Biophys. Res. Commun. 295, 119–124 (2002).

  114. 114.

    et al. Circulating anti-galectin-1 antibodies are associated with the severity of ocular disease in autoimmune and infectious uveitis. Invest. Ophthalmol. Vis. Sci. 47, 1550–1556 (2006).

  115. 115.

    et al. Role of galectin-3 in mast cell functions: galectin-3-deficient mast cells exhibit impaired mediator release and defective JNK expression. J. Immunol. 177, 4991–4997 (2006).

  116. 116.

    et al. Galectin-3 functions as an adhesion molecule to support eosinophil rolling and adhesion under conditions of flow. J. Immunol. 179, 7800–7807 (2007).

  117. 117.

    et al. Galectin-9 inhibits CD44–hyaluronan interaction and suppresses a murine model of allergic asthma. Am. J. Respir. Crit. Care Med. 176, 27–35 (2007).

  118. 118.

    & Transcriptional regulation of galectin-10 (eosinophil Charcot–Leyden crystal protein): a GC box (-44 to -50) controls butyric acid induction of gene expression. Life Sci. 69, 201–212 (2001).

  119. 119.

    et al. Functional characterization of an eosinophil-specific galectin, ovine galectin-14. Glycoconj. J. 23 Sept 2008 (10.1007/s10719-008-9190-0).

  120. 120.

    & Glycans in cancer and inflammation — potential for therapeutics and diagnostics. Nature Rev. Drug Discov. 4, 477–488 (2005).

  121. 121.

    & Galectins as modulators of tumour progression. Nature Rev. Cancer 5, 29–41 (2005).

  122. 122.

    , , & Galectins in the tumor endothelium: opportunities for combined cancer therapy. Blood 110, 2819–2827 (2007).

  123. 123.

    et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; a potential mechanism of tumor-immune privilege. Cancer Cell 5, 241–251 (2004).

  124. 124.

    et al. O-glycosylation regulates LNCaP prostate cancer cell susceptibility to apoptosis induced by galectin-1. Cancer Res. 67, 6155–6162 (2007).

  125. 125.

    et al. Galectin-1: a link between tumor hypoxia and tumor immune privilege. J. Clin. Oncol. 23, 8932–8941 (2005).

  126. 126.

    , , , & Tumor-associated galectin-3 modulates the function of tumor-reactive T cells. Cancer Res. 68, 7228–7236 (2008).

  127. 127.

    et al. Galectin-3 expression correlates with apoptosis of tumor-associated lymphocytes in human melanoma biopsies. Am. J. Pathol. 168, 1666–1675 (2006).

  128. 128.

    et al. Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein–Barr virus-infected nasopharyngeal carcinoma cells. Blood 113, 1957–1966 (2009).

  129. 129.

    et al. Anti-galectin compounds as potential anti-cancer drugs. Curr. Med. Chem. 13, 3513–3527 (2006).

  130. 130.

    et al. Galectin-3 is a negative regulator of lipopolysaccharide-mediated inflammation. J. Immunol. 181, 2781–2789 (2008).

  131. 131.

    et al. Regulated expression of galectin-1 during T-cell activation involves Lck and Fyn kinases and signaling through MEK1/ERK, p38 MAP kinase and p70S6 kinase. Mol. Cell. Biochem. 267, 177–185 (2004).

  132. 132.

    et al. Activated rat macrophages produce a galectin-1-like protein that induces apoptosis of T cells: biochemical and functional characterization. J. Immunol. 160, 4831–4840 (1998).

  133. 133.

    et al. Expression and function of galectin-3, a β-galactoside-binding protein in activated T lymphocytes. J. Leukoc. Biol. 69, 555–564 (2001).

  134. 134.

    et al. Specific recognition of Leishmania major poly-β-galactosyl epitopes by galectin-9: possible implication of galectin-9 in interaction between L. major and host cells. J. Biol. Chem. 278, 22223–22230 (2003). This study provides mechanistic insights into the role of galectin–glycan lattices in host–pathogen interactions.

  135. 135.

    et al. LacdiNAc-glycans constitute a parasite pattern for galectin-3-mediated immune recognition. J. Immunol. 173, 1902–1907 (2004).

  136. 136.

    et al. Novel innate immune functions for galectin-1: galectin-1 inhibits cell fusion by Nipah virus envelope glycoproteins and augments dendritic cell secretion of proinflammatory cytokines. J. Immunol. 175, 413–420 (2005).

  137. 137.

    et al. Galectin-1 promotes HIV-1 infectivity in macrophages through stabilization of viral adsorption. Virology 371, 121–129 (2008).

  138. 138.

    et al. Galectin-3 binds lactosaminylated lipooligosaccharides from Neisseria gonorrhoeae and is selectively expressed by mucosal epithelial cells that are infected. Cell. Microbiol. 4, 649–662 (2002).

  139. 139.

    et al. Specific recognition of Candida albicans by macrophages requires galectin-3 to discriminate Saccharomyces cerevisiae and needs association with TLR2 for signaling. J. Immunol. 177, 4679–4687 (2006).

  140. 140.

    , , , & Galectin-3 induces death of Candida species expressing specific β-1,2-linked mannans. J. Immunol. 177, 4718–4726 (2006).

  141. 141.

    et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27, 3746–3753 (2008).

  142. 142.

    et al. Induction of cell adhesion by galectin-8 and its target molecules in Jurkat T-cells. J. Biochem. 143, 311–324 (2008).

  143. 143.

    et al. Effects of N-glycan processing inhibitors on signaling events and induction of apoptosis in galectin-1-stimulated Jurkat T lymphocytes. Glycobiology 16, 1262–1271 (2006).

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Acknowledgements

We apologize to the many authors whose papers could not be cited owing to space limitations. We are grateful to H.F. Rosenberg for critical reading of the manuscript and D. Croci for help in manuscript preparation. We also thank J. Ilarregui, M. Salatino and G. Bianco for critical discussions. The authors are supported by grants from The Cancer Research Institute Elaine R. Shephard Award (USA), The Mizutani Foundation for Glycoscience (Japan), The Prostate Cancer Foundation (UK), Fundación Sales (Argentina), Agencia Nacional de Promoción Científica y Tecnológica (FONCYT, PICT grant number 2006-603; Argentina), Universidad de Buenos Aires (M091) and Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina).

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Affiliations

  1. Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428, Ciudad de Buenos Aires, Argentina.

    • Gabriel A. Rabinovich
    •  & Marta A. Toscano
  2. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428, Ciudad de Buenos Aires, Argentina.

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  1. Search for Gabriel A. Rabinovich in:

  2. Search for Marta A. Toscano in:

Corresponding author

Correspondence to Gabriel A. Rabinovich.

Supplementary information

Glossary

Lattice

Spatial array of glycans and endogenous multivalent lectins on the cell surface that controls signalling and cellular responses.

Anergy

A state of non-responsiveness to antigen. Anergic B or T cells cannot responds to their cognate antigens under optimal conditions of stimulation.

C-type lectin

A receptor protein that binds carbohydrates in a calcium-dependent manner. The binding activity of C-type lectins is based on the structure of the carbohydrate recognition domain.

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell (APC); it consists of molecules required for adhesion and signalling. This structure is important in establishing T cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.

Negative selection

One step in the process of T cell differentiation in the thymus. Cells that express T cell receptors with high affinity for self antigens are eliminated from the repertoire by apoptosis after recognition of their target antigen presented by thymic dendritic cells.

Central tolerance

Tolerance created at the level of the central lymphoid organs. For T cells, positive and negative selection occurs in the thymus.

Peripheral tolerance

The lack of self-responsiveness of mature lymphocytes to specific antigens in the periphery. These mechanisms control potentially self-reactive lymphocytes that have escaped central tolerance mechanisms and prevent exuberant inflammatory reactions.

TH cells

Subsets of activated CD4+ T cells that are specialized in different functions. T helper 1 (TH1) cells produce interleukin-2 (IL-2), interferon-γ and lymphotoxin and support cell-mediated immune responses. TH2 cells produce IL-4, IL-5, IL-10 and IL-13, support antibody-mediated immune responses and downregulate TH1 and TH17 cell responses. TH17 cells produce IL-17A, IL-17F, IL-21 and IL-22 and are important in inflammatory and autoimmune diseases.

Alternative activation

A process triggered by interleukin-4 (IL-4) and IL-13 in macrophages that determines the development of T helper 2 (TH2)-type responses, in contrast to classical activation, which is typically mediated by interferon-γ and is essential for the microbicidal activity of macrophages and the promotion of TH1-type responses.

Experimental autoimmune encephalomyelitis

An inflammatory demyelinating disease of the central nervous system, which shows pathological and clinical similarities to multiple sclerosis.

Graft-versus-host disease

An immune response mounted against the recipient of an allograft (generally in the context of allogeneic bone marrow transplantation) by donor T cells that are derived from the graft.

Exosome

A small lipid bilayer vesicle that is made up of plasma membrane or membrane derived from intracellular vesicles that are released from different cell types.

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DOI

https://doi.org/10.1038/nri2536

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