For example, T cells from mice deficient in Mgat5, which encodes a glycosyltransferase involved in generation of galectin-binding epitopes, have enhanced T-cell receptor (TCR) clustering at the immunological synapse and increased TCR signaling 22.
These proteins have emerged as important regulators of the immune response. Indeed, the galectin lattice influences glycoprotein compartmentalization and lateral mobility at the cell surface 19, 20, 21. Several mechanisms have been identified that impact on the organization and mobility of membrane proteins, including the actin cytoskeleton 11, 12, 13, protein–protein interactions 9, 14, 15, 16, and membrane microdomains defined by lipid composition 8, 17.Īn often overlooked mechanism controlling membrane protein organization and mobility is the interaction of these cell surface glycoproteins with the family of soluble secreted lectins, known as galectins, which bind and crosslink cell surface proteins, generating glycan-based domains 18. These parameters have important implications for receptor triggering and the assembly of signaling complexes as they influence the interaction between protein partners. Two key parameters influencing the assembly of signaling clusters and regulation of membrane receptor activation are the constitutive nanoscale clustering of membrane proteins referred to as nanoclusters or protein islands 8, 9, 10, and the cell surface mobility of membrane proteins (or nanoclusters of proteins) 7, 11, 12. Indeed, the size and spatial patterning of signaling assemblies significantly contribute to cellular outcomes, with even small variations resulting in altered responses 5, 6, 7. These observations implicate receptor clustering as a mechanism to regulate signaling events, and consequently the cellular outcome of receptor engagement. Similar microstructures of antigen receptors have been described in T cells 3 and thus have been proposed to represent the basic unit of lymphocyte signaling 4. B-cell activation is accompanied by formation of numerous signaling microclusters 2.
B-cell activation is triggered by binding of antigen to the B-cell receptor (BCR), which initiates a cascade of intracellular signaling through assembly of a multiprotein complex of kinases and adaptors 1. In resting naive cells, we use dual-color super-resolution imaging to demonstrate that galectin-9 mediates the close association of IgM and CD22, and propose that the loss of this association provides a mechanism for enhanced activation of galectin-9-deficient B cells.ī cells play a critical role in the immune response and production of protective antibodies.
We show that galectin-9 merges pre-existing nanoclusters of IgM-BCR, immobilizes IgM-BCR, and relocalizes IgM-BCR together with the inhibitory molecules CD45 and CD22. We investigated the molecular mechanism for galectin-9-mediated inhibition of BCR signaling using super-resolution imaging and single-particle tracking. Notably, treatment with exogenous recombinant galectin-9 nearly completely abolishes BCR signaling. Furthermore, we show enhanced BCR microcluster formation and signaling in galectin-9-deficient B cells. Here we identify IgM-BCR as a ligand for galectin-9. The galectin family of secreted lectins have emerged as important regulators of immune cell function however, their role in B-cell responses is poorly understood.
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