Age-related remodeling of the sialoglycans dampens murine CD8 ⁺ T cell function

Glycans regulate cellular function, yet how aging affects the glycocalyx remains unclear. Here, we investigate changes in immune cell glycocalyx with age and find that α2,6-linked sialic acid, a glycan epitope associated with inhibitory signaling, is down-regulated in T cells from old animals. This reduction is tightly correlated with age-associated accumulation of effector T cells, which have little to no α2,6-linked sialic acid. To understand how α2,6-linked sialic acid affects T cell physiology, we generated a mouse model with T cell-specific deletion of sialyltransferase gene <i>St6gal1</i>. The lack of α2,6-linked sialic acid leads to reduced responsiveness in naïve T cells, leading to impaired T cell responses against <i>Listeria monocytogenes</i> infection and tumor growth. PD-1 pathway blockade partially restores <i>St6gal1</i>-deficient T cells' ability to control tumor growth. These findings suggest that α2,6-linked sialic acid is critical for maintaining long-term T cell responsiveness, and its loss may contribute to decreased T cell function with age.