Featured Articles

Lymphocytes: T helpers' sugar signature

Spleen sections from wild-type and Lgals1^-/- mice (right) show that Lgals1^-/- mice have fewer apoptotic CD4⁺ T cells (green) in spleen sections than wild-type mice (left).

CD4⁺ T cells develop into three types of T helper cell upon antigen presentation - T_H1, T_H-17 and T_H2 cells. Until now, the factors controlling differentiation and expansion of T helper cell subpopulations are relatively well understood. However, limited information is available on the homeostatic signals that differentially influence the fate of these cells. In Nature Immunology Toscano et al. investigate whether different carbohydrate ligands may influence the survival of T_H1, T_H-17 and T_H2 cells upon exposure to the carbohydrate binding protein Galectin-1, which has been shown to be highly produced by immunoregulatory CD4⁺CD25⁺ cells.

The authors observed in vitro that human T_H1, but not T_H2 cells, underwent apoptosis after exposure to Galectin-1. This reaction was specific for Galectin-1 as incubation with a general apoptosis-inducing reagent led to apoptosis in both cell types. Lectin binding studies indicated that T_H2 cell glycans contain an 2,6-linked sialic acid that blocks Galectin-1 binding and apoptosis. This finding was mirrored by the fact that  galactoside 2,6 sialyltransferase 1(ST6Gal1) expression was upregulated in T_H2 cells. Thus, sialylation of T_H2 cells prevents apoptosis, while T_H1 exposes the N-acetyllactosamine glycan epitope that serves as a ligand for Galectin-1. The authors replicated their findings in vivo using T_H1 and T_H2 cells generated by pathogen-derived antigen injection into mice. The authors also  found that T_H-17 cells generated from CD4⁺ cells in vitro expressed a similar glycan motif as T_H1 cells.

Toscano et al. observed that Galectin-1 knockout (Lgals1^-/-) mice developed a hyper T_H1 response upon injection of bacteria, however, T_H2 proliferation in Lgals1^-/- and wild-type mice was unchanged. These results point to a central role for Galectin-1 in the control of T_H1 cell expansion. Likewise, experimental autoimmune encephalomyelitis (EAE) was significantly more severe in Lgals1^-/- than in wild-type mice and could be lessened by Galectin-1 injection. Lgals1^-/- splenocytes showed increased proliferation than wild-type mice, as well as increased interleukin-17 and interferon- production, while T_H2 cytokine concentrations remained unchanged. Lectin analysis revealed a higher percentage of lymphocytes with terminal galactose, which was reduced upon injection of Galectin-1. These results suggest that specific interactions between galectin-1 and its carbohydrate ligands are involved in the negative regulation of the autoimmune response mediated by T_H1 and T_H-17 cells.

The study of Toscano et al. offers an explanation for the shift toward T_H2 cell differentiation observed upon administration of galectin-1 in several models of autoimmune disease. Future research is needed to pinpoint specific functions for other members of the galectin family on modulation of T_H1- and T_H-17-mediated immune responses, yet this study allows the visualization of strategies through which the manipulation of T-cell glycosylation may provide an avenue for treatment of autoimmune diseases.

Author: Mirko von Elstermann