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Modulating immune cell development: Polysialic acid sticks out

Polysialic acid (polySia) is an unusual glycan modification first identified on neuronal cells, where polysialylation of the neural adhesion molecule (NCAM) regulates migratory processes during neuronal development. PolySia has also been found to modify neuropilin on neuronal and dendritic cells. Now in the Journal of Immunology, Drake et al. demonstrate that both human and murine leukocytes carry polySia and that this expression is correlated with immune function.

Distribution of newborn neurons and expression of galectin-1 in the dentate gyrus after kainate administration. DAPI (i, m; blue), galectin-1 (j, n; red), PSA-NCAM (k, o; green), and their merged images are shown (l, p). Figure taken from Cell Death and Differentiation advance online publication 14 November 2008; doi: 10.1038/cdd.2008.162

Drake et al. used flow cytometric analyses to show that human natural killer (NK) cells express polysialylated NCAM. Interleukin-2 activation of NK cells increases the cell surface levels of both polySia and NCAM. Additionally, the length of polySia varies widely on resting NK cells, but becomes more uniform upon activation. Thus, the structure of this glycan moiety appears to vary with immune cell activation.

The authors observed differential expression of polySia in the mouse immune system as compared to the human. In the mouse, polySia was identified on subsets of bone marrow cells including multipotent progenitors and differentiating myeloid cells. Mouse NK cells did not express polySia. The polysialyltransferase ST8Sia IV, which generates polySia, was demonstrated to be the enzyme responsible for leukocyte expression of polySia in the mouse.

Drake et al. went on to investigate whether a lack of polySia alters immune reactions using ST8Sia IV^-/- mice. An assay testing contact hypersensitivity, a response similar to that induced by poison ivy, demonstrated that ST8Sia IV^-/- mice generate exaggerated inflammation as compared to wild-type mice. Furthermore, in a tumor model, ST8Sia IV^-/- mice generate exaggerated inflammation as compared to wild-type mice. Tumors grew in the ST8Sia IV^-/- mice at a rate comparable to that of the immunocompromised T-cell receptor ^-/- mice, which lack an important T-cell compartment.

Taken together, the results of Drake et al. show that polySia is present on different leukocyte subsets in humans and mice, where it influences inflammatory reactions and tumor response. The authors hypothesize that the actions of polySia may parallel those of glycosaminoglycans — another class of polysaccharides that carry multiple negative charges and modify the activity of small, positively charged ligands such as cytokines, chemokines and growth factors, all important players in immune development and response.

Author: Mirko von Elstermann