Immune receptors are not randomly distributed at the plasma membrane of lymphocytes but are segregated into specialized domains that function as platforms to initiate signalling, as exemplified by the B cell or T cell receptor complex and the immunological synapse. ‘Membrane-organizing proteins’ and, in particular, tetraspanins and galectins, are crucial for controlling the spatiotemporal organization of immune receptors and other signalling proteins. Deficiencies in specific tetraspanins and galectins result in impaired immune synapse formation, lymphocyte proliferation, antibody production and migration, which can lead to impaired immunity, tumour development and autoimmunity. In contrast to conventional ligand–receptor interactions, membrane organizers interact in cis (on the same cell) and modulate receptor clustering, receptor dynamics and intracellular signalling. New findings have uncovered their complex and dynamic nature, revealing shared binding partners and collaborative activity in determining the composition of membrane domains. Therefore, immune receptors should not be envisaged as independent entities and instead should be studied in the context of their spatial organization in the lymphocyte membrane. We advocate for a novel approach to study lymphocyte function by globally analysing the role of membrane organizers in the assembly of different membrane complexes and discuss opportunities to develop therapeutic approaches that act via the modulation of membrane organization.
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The authors dedicate this review to S. Levy (Stanford University School of Medicine) who made seminal contributions to the field of tetraspanins in the immune system. The authors thank P. Friedl and C. Figdor (Radboud University Medical Center) for useful discussions and careful review of the manuscript. The authors acknowledge funding support from the Netherlands Organization for Scientific Research: the Institute of Chemical Immunology (project ICI 000-23 to F.S. and A.B.v.S.), ZonMW (project 09120012010023) to A.B.v.S., the Dutch Cancer Society (project 11618 to L.Q.C. and A.B.v.S., and 12949 and 14726 to A.B.v.S.), and the European Research Council: Consolidator Grant (project 724281) and Proof-of-Concept (project 101112687) to A.B.v.S.
The authors declare no competing interests.
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- β-Galactoside modifications
Modifications introduced by the enzyme β-galactoside, which cleaves the disaccharide lactose to produce galactose and glucose.
- Fluid mosaic model
A model proposed by Singer and Nicolson in 1972 describing the plasma membrane as a dynamic structure in which membrane proteins are clustered into non-random domains.
- Galectin lattices
Multivalent complexes of soluble galectins with glycoproteins on the plasma membrane. Galectin lattices may contain different members of the galectin family, but individual galectins can also form distinct lattices.
A specialized dense coating composed of a mixture of glycoproteins, glycosaminoglycans and proteoglycans that covers the cell surface.
- Immune synapses
Stable interfaces that form the site of the molecular interactions between a lymphocyte and an antigen-presenting cell. The formation of an immune synapse is important for the induction of lymphocyte activation and polarization.
- Integrin inside-out signalling
Signalling induced by the binding of signalling molecules or components of the cytoskeleton to the intracellular domain of integrins. This can induce conformational changes in the extracellular portion of the integrin and activate the ligand-binding function.
- Lipid rafts
Cholesterol and sphingolipid-enriched membrane domains that favour the presence of specific proteins.
- Membrane domains
Ordered regions of the plasma membrane formed by the lateral segregation of its constituents that differs from the surrounding area in its molecular organization and composition.
- Membrane organizers
Proteins that affect the spatiotemporal organization of other membrane proteins and/or signalling proteins, independent of other factors.
(LacNAcs). Disaccharide synthesized from linking N-acetylglucosamine and galactose. LacNAcs are present on many glycoproteins and function as a carbohydrate-binding site.
- N-linked glycans
Attachments of an oligosaccharide to a protein at asparagine residues by an N-glycosidic bond.
- O-linked glycans
Attachments of an oligosaccharide to the oxygen atom of serine or threonine residues in a protein.
- Supramolecular activation cluster
(SMAC). A focalized region of receptor–ligand interaction and signalling machinery in T cells interacting with antigen-presenting cells. Proteins segregate into distinct regions, a central area (cSMAC) enriched in the T cell receptor and associated proteins, a peripheral area (pSMAC) containing LFA1 and talin, and a distal region (dSMAC) enriched in CD45 and F-actin.
- Tetraspanin nanodomains
Specialized membrane regions composed of tetraspanins and associated membrane and signalling proteins.
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Querol Cano, L., Dunlock, VM.E., Schwerdtfeger, F. et al. Membrane organization by tetraspanins and galectins shapes lymphocyte function. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00935-0