Research Highlights

T cell development: Fate sealed in sugar

To mature into adequate immune defenders, developing T cells must be able to recognize foreign antigens, but tolerate self-antigens. To prevent immunodeficiencies or autoimmune reactions, cells that do not meet those criteria are eliminated. Galectin-1 is a glycan-binding protein that helps to regulate T cell selection by binding to cell-surface ligands and triggering apoptosis. A new study in the Journal of Biological Chemistry finds that galectin-1-mediated cell death can be controlled in part by the composition of O- and N-glycans found on CD45, a major galectin-1 ligand on the T cell surface.

CD45 is found in several different forms that vary in glycosylation and galectin-1 binding affinity. B cells express CD45 variants with a full complement of O-glycans, whereas T cells vary in their extent of CD45 O-glycosylation, particularly at different stages of maturation. Linda Baum and colleagues now show that T cells expressing CD45 decorated with one type of O-glycan, Core 2, are more susceptible to galectin-1 binding, which leads to inhibition of CD45 phosphatase signaling, and induction of apoptosis. When Core 2 was added to CD45 variants with low levels of O-glycan, galectin-1-mediated inhibition of phosphatase signaling was restored. In the complete absence of Core 2 on CD45, galectin-1 binding could be induced by overexpression of a different type of O-glycosylation, Core 1. Susceptibility to galectin-1 could also be enhanced in Core 2-deficient T cells by inhibiting CD45 phosphatase activity.

Galectin-1 recognition of CD45 is also influenced by the arrangement of N-glycans on the glycoprotein. CD45 N-glycans terminate in sialic acid residues that can be either α2,3- or α2,6-linked, and the authors used the Consortium for Functional Glycomics glycan microarray to explore galectin-1 binding to N-glycans with various sialic acid linkages. They found that galectin-1 binding is increased in cells with the α2,3 linkage, whereas CD45 with α2,6-linked sialic acids promotes resistance to galectin-1, protecting T cells from apoptosis. Thus, small shifts in N-glycan composition can greatly affect T cell vulnerability to galectin-1-mediated cell death. In contrast to Core 2 O-glycans, resistance to galectin-1 induced by α2,6-linked sialic acids was not dependent on CD45 phosphatase activity and sensitivity could not be restored by treatment with a phosphatase inhibitor. These results suggest that when CD45 lacks Core 2, the preferred ligand motif of galectin-1, it compensates by binding other cell surface receptors.

The fine-tuning of O- and N-glycan expression on CD45 is a carefully controlled mechanism that directs T cell development and function. This study of the complex interplay between CD45 sugars and galectin-1 in the immune system helps pinpoint the underlying causes of autoimmune and immunodeficiency diseases.

Author: Heather Buschman