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T-cell development: The sweet face of death

Galectins in cell-cell communication and signaling. Click here for a larger picture. From Liu, F. T. & Rabinovich, G. A. Galectins as modulators of tumour progression. Nat. Rev. Cancer 5, 29-41 (2005).

Maturation, activation, and migration of T cells are influenced by protein-glycan interactions. Two studies now show that the interactions of galectins with glycan ligands are central components of the signaling pathways determining T-cell development.

Bi et al.—reporting in the Journal of Biological Chemistry—observed that Gal-1, but not Gal-9, required core 2 O-glycans and cluster of differentiation (CD) markers such as CD7 to elicit apoptosis in various human and murine T-cell lines. Furthermore, Bcl-2 expression reduced cell death induced by Gal-9 but not by Gal-1. This indicates that Gal-9 and Gal-1 activities are restricted by different glycans and glycoprotein receptors on the T-cell surface, and that each of the galectins initiates different apoptotic signaling pathways. Moreover, although Gal-1 was homogeneously distributed throughout the thymus, Gal-9 was more abundant in epithelial cells than in cortical thymus regions.

Next, the authors generated chimeric galectins to identify which structural features of the rigid Gal-1 homodimer and of the flexibly linked bivalent Gal-9 are responsible for the different apoptotic effects. A construct in which the C terminus, formed by the C-terminal Gal-9 CRD, was linked by the flexible Gal-9 linker to the Gal-1 CRD at the amino (N) terminus was as potent as native Gal-9 in inducing apoptosis. On the other hand, inserting the Gal-1 CRD at the C-terminus resulted in a molecule that behaved like native Gal-1. Bi et al. conclude that the C-terminal CRDs of the constructs control ligand use and apoptosis pathway determination. Second, they hypothesize that Gal-9's broader ligand specificity and flexibly linked structure are responsible for its stronger apoptotic potency.

A separate study by Liu et al. in Blood details the consequences of Gal-1-induced apoptosis in the double-positive stage of T-cell maturation. The authors used H-Y mice, which express a TCR exclusively specific for the male H-Y antigen. This leads to positive selection of H-Y⁺ CD8⁺ T cells in female mice, and, because of the presence of autoantigenic HY, a strong decrease in H-Y⁺ CD8⁺ T cells in male mice by negative selection. In mice lacking Gal-1 (Gal-1^-/-), both sexes showed a strong increase in H-Y⁺ CD8⁺ T cells. These results indicate that the apoptotic activity of Gal-1 promotes negative and antagonizes positive selection of double-positive CD8⁺ T cells.

Weak yet sustained extracellular signal-regulated kinase (ERK) activation, measured by the concentration of phosphorylated ERK (pERK), controls the positive selection of double-positive T cells, whereas a short burst of ERK phosphorylation leads to negative selection. Liu et al. found more pERK in double-positive wild-type and Gal-1^-/- T cells after incubation with Gal-1 in a mouse model of negative selection. In contrast, they found less pERK in normal double-positive than in Gal-1^-/- T cells in a model of positive selection. Thus Gal-1 causes opposite changes of pERK concentration in each of the T-cell fate decisions. Liu et al. hypothesize that a different use of ligands acting as T-cell antigen co-receptors in each of the selection conditions may be translated into the activation of different mitogen-activated protein kinase pathway components upstream of ERK.

Author: Mirko von Elstermann