Polysialic acid (polySia) is a highly regulated polymer of sialic acid (Sia) with such potent biophysical characteristics that when expressed drastically influences the interaction properties of cells. Although much of what is known of polySia in mammals has been elucidated from the study of its role in the central nervous system (CNS), polySia is also expressed in other tissues, including the immune system where it presents dynamic changes during differentiation, maturation, and activation of different types of immune cells of the innate and adaptive response, being involved in key regulatory mechanisms. At least six polySia protein carriers (CCR7, ESL-1, NCAM, NRP2, ST8Sia 2, and ST8Sia 4) are expressed in different types of immune cells, but there is still much to be explored in regard not only to the regulatory mechanisms that determine their expression and the structure of polySia chains but also to the identification of the cis- and trans- ligands of polySia that establish signaling networks. This review summarizes the current knowledge on polySia in the immune system, addressing its biosynthesis, its tools for identification and structural characterization, and its functional roles and therapeutic implications.

CD4+ T helper lymphocytes (Th) orchestrate the immune response after their activation by antigen-presenting cells. Activation of naïve Th cells is reported to generate the reduction in surface epitopes of sialic acid (Sia) in α2,3 and α2,6 linkages. In this work, we report that in spite of this glycophenotype, anti-CD3/anti-CD28-activated purified human naïve Th cells show a significant increase in surface Sia, as assessed by metabolic labeling, compared with resting naïve Th cells, suggesting an increased flux of Sia toward Siaα2,8 glycoconjugates. To understand this increase as a result of ganglioside up-regulation, we observed that very early after activation, human naïve Th cells show an increased expression in surface GD3 and neoexpression of surface GD2 gangliosides, the latter clustering with the T cell receptor (TCR). Also, we report that in contrast to GM2/GD2 synthase null mice, lentiviral vector-mediated silencing of the GM2/GD2 synthase in activated human naïve Th cells reduced efficient TCR clustering and downstream signaling, as assessed by proliferation assays and IL-2 and IL-2R expression, pointing to an important role of this enzyme in activation of human naive Th cells.

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