Key Points
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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.
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Galectin–glycoprotein interactions form a multivalent 'lattice' that controls glycoprotein clustering and endocytosis to regulate receptor signalling and activation.
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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.
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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.
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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.
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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.
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.
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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.
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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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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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Rabinovich, G., Toscano, M. Turning 'sweet' on immunity: galectin–glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 9, 338–352 (2009). https://doi.org/10.1038/nri2536
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DOI: https://doi.org/10.1038/nri2536
