Polysialylation is a general feature of immune activation

Sialic acids are critical regulators of immune responses and the sialic acid-Siglec axis has receive much attention recently for it role as a new immune checkpoint. While 2,3- and 2,6-linked sialosides have been well studied, much less is known about the 2,8-linked polysialic acid (polySia), especially in the adaptive immune system. We demonstrate here that polySia is actually found in all major classes of circulating immune cells, including B and T cells, where it is strongly associated with prior antigen exposure. Cell surface expression of polySia could be observed within 24 h of activation of naive T cells but did not correlate with expression of the immune-specific polysialyltransferase ST8Sia4. Finally, we assessed the effects of smoking on polySia levels, and noted substantial increased levels of polySia, particularly on effector T cells and preferentially in males. Significance StatementThe immune system is central to human health and holds the key to treating many chronic diseases. We show for the first time that the immunomodulatory glycan polysialic acid is widespread in the human immune system and associated with immune cell activation. Moreover, sex-dependent increases in polysialic acid could be observed on key populations of immune effector cells in smokers. This study offers insight into how glycans might contribute to sex differences in development and progression of chronic diseases.