T cells bet on sugars to help

Comment on Underhill et al, page 3867

Leukocytes emigrate into inflamed tissues by binding to selectins on endothelial cells; while different leukocyte subsets traffic to different tissue sites, the mechanisms regulating selective expression of selectin ligands on specific cell subsets are not known. Underhill and colleagues demonstrate that the signals that drive Th1 cell differentiation also drive expression of the glycosyltransferase enzymes that create selectin ligands on these cells.

Two important scientific advances occurred about 20 years ago. First, T-helper 1 (Th1) and Th2 subsets of CD4 T-helper cells were described.¹  Second, lectin-carbohydrate–mediated cell adhesion was shown to be the initial step in extravasation of leukocytes at sites of inflammation.²  In subsequent years, several groups have noted homing of Th1 and Th2 cells to different tissue sites, mediated by specific selectin-ligand interactions between T cells and endothelial cells. In this issue of Blood, Kansas's group has identified components of the cellular signaling program that instructs Th1 cells to specifically display the cell surface saccharide ligands recognized by endothelial cell selectins.

Th1 and Th2 cells are derived from naive CD4 T cells, and differentiation of a naive CD4 T cell into a Th1 or Th2 cell is regulated by specific transcription factors, such as signal transducer and activator of transcription 4 (Stat4) and T-bet in Th1 cells and GATA-3 in Th2 cells. In addition to differences between Th1 and Th2 subsets in cytokine production and responses to antigens, Th1 cells preferentially home to inflammatory sites in peripheral tissues. Preferential trafficking of Th1 cells to inflammatory sites results from expression on Th1 cells, but not Th2 cells, of high levels of saccharide ligands recognized by selectins on endothelial cells.

Selectins mediate leukocyte rolling, allowing the leukocyte to attach to endothelial cells and infiltrate into the underlying tissue. Selectins can be expressed on leukocytes, such as L-selectin on lymphocytes, or on endothelial cells, such as E-selectin and P-selectin; conversely, oligosaccharide ligands recognized by selectins are displayed by endothelial cells for L-selectin or leukocytes for E- and P-selectins. The basic selectin ligand is a tetrasaccharide, Siaα2,3Galβ1,4(Fucα1,3)GalNAc (ie, sialyl Le^x),³  that can be presented on different leukocyte and endothelial cell glycoprotein backbones (see bottom of figure). Identification of the tetrasaccharide ligand suggested candidate glycosyltransferase enzymes that could make the structure. Analysis of mice deficient in specific glycosyltransferases confirmed that these enzymes could create the tetrasaccharide ligands required for selectin-mediated leukocyte trafficking and identified subtle differences in modifications of the tetrasaccharide to promote recognition by different selectins.^4,5  However, the cellular mechanisms that control coordinated expression of the glycosyltransferases in vivo to create the tetrasaccharide ligands remained unknown.FIG1 

Because the roles of T-bet and Stat4 in Th1 polarization are established, and because candidate glycosyltransferases that can create selectin ligands have been identified, Underhill and colleagues examined the roles of T-bet and Stat4 in upregulating expression of these candidate glycosyltransferases during Th1 polarization. In addition, to confirm that the glycosyltransferases are responsible for creating selectin ligands, Th1 cells generated from mice deficient in specific glycosyltransferases were analyzed. As structural analysis of oligosaccharide structures is technically challenging and requires amounts of material difficult to obtain from primary T cells, creation of oligosaccharide ligands on Th1 cells was shown by functional assays (ie, T-cell rolling on monolayers of cells expressing E- or P-selectin). This functional approach allowed identification of ST3Gal-VI (α 2,3-sialyl-transferase VI) as a novel glycosyltransferase involved in synthesis of selectin ligands on Th1 cells. More important, these investigators' past and current work are now synthesized in a model integrating signaling from T-cell and interleukin 12 (IL-12) receptors with transcriptional regulation resulting in coordinated expression of 4 different glycosyl-transferases that create functional selectin ligands on cell surface glycoproteins (see figure).

In the emerging field of glycobiology, mechanistic connection of cell signaling to the synthesis of specific oligosaccharide ligands during differentiation is an exciting and important advance. As oligosaccharides on glycoproteins and glycolipids cover much of the surface of mammalian cells and regulate cell adhesion, migration, proliferation, and survival, future studies will no doubt demonstrate that signals regulating cellular glycosylation are critical for the differentiation and function of all hematopoietic cells. ▪