Age-related remodeling of the glycocalyx drives T cell exhaustion

Cell surface glycans, termed the glycocalyx, are essential regulators of cellular signaling and thus cellular development and functions, but how aging impacts the glycocalyx remains poorly understood. Here, using immune cells as a model system for studying the relationship between aging and glycocalyx remodeling, we show that 2,6-linked sialic acid - a terminal glycan epitope typically associated with inhibitory signaling - becomes downregulated in T cells from older animals. This downregulation is tightly correlated with age-associated accumulation of effector T cells, which are decorated with little to no 2,6-linked sialic acids. T cell aging renders older individuals more vulnerable to infections and cancers. To understand the role of 2,6-linked sialic acids in T cell physiology, we generated a mouse model with T cell-specific deletion of the sialyltransferase gene St6gal1. The chronic depletion of 2,6-linked sialic acids led to naive T (TN) cells expansion in the periphery and premature T cell exhaustion. As a result, these mice were less able to control acute Listeria infection and chronic tumor growth. Blockade of the PD-1 pathway can partially restore the ability of St6gal1-deficient T cells to control tumor growth. Together, these data suggest that 2,6-linked sialic acids are critical for maintaining long-term T cell responsiveness, and the loss of 2,6-linked sialic acids may directly contribute to age-related T cell exhaustion.