Sialoglycans on human T cells attenuate death programs executed through the Fas pathway.

T cells are critical executors of adaptive immune responses and their persistence is tightly regulated. Part of this regulation relies on programmed cell death driven by the tumor necrosis factor (TNF) receptor superfamily. The addition of glycans that terminate in α2-6-linked sialic acids (sialoglycans) to these cell death receptors has been shown to attenuate their apoptotic functions. While this is now understood to be a pro-survival mechanism in settings of cancer pathophysiology, the specific roles of sialoglycans in regulating cell death receptor activity on human T cells remain unexplored. This is of particular importance, given the rising interest in T cell glycan editing for therapeutic benefit. Here, we show that loss of α2-6-sialoglycans in an immortalized T cell line (ST6GAL1(-/-) Jurkat) attenuated apoptosis induced by the Fas receptor (FasR). This effect was less pronounced for other TNF receptor superfamily members (TNFR1 and TRAIL-R1). Reorganization of FasR-a process required for apoptotic signaling-was more limited on ST6GAL1(-/-) Jurkat cells compared to WT controls. These findings were further supported by phosphoproteomics results, which confirmed that loss of sialoglycans negatively regulated the pro-survival MAPK/ERK signaling pathway. Finally, we used a recombinant sialic acid cleaving enzyme (sialidase) to confirm that sialoglycans on primary human T cells are bona fide immunophysiological regulators of FasR-driven programmed cell death. Combined, our results demonstrate that sialoglycans on T cells influence cell fate driven by the Fas pathway and provide motivation to further characterize the immunoregulatory roles of the glycocalyx in health and disease.