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Published on: October 20, 2023
Sialoglycans on human T cells attenuate death programs executed through the Fas pathway
Abstract:
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 the monosaccharide sialic acid (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 remains unexplored. This is of particular importance given the rising interest in T cell glycan editing for therapeutic benefit. Here, we address this gap using both immortalized (Jurkat) and primary human T cells deficient in sialoglycans. We found that T cell sialoglycans suppressed apoptosis induced by the Fas receptor (FasR) but not other TNF receptor superfamily members such as TNFR1 and TRAIL-R1. Dynamic reorganization of FasR was increased on sialoglycan-deficient Jurkat cells, suggesting that these glycans limit receptor clustering. This model was further supported by phosphoproteomics results, which confirmed that loss of sialoglycans negatively regulated the pro-survival MAPK/ERK signalling 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 sialoglycan remodelling on T cells influences cell fate driven by the Fas pathway and provide motivation to further characterize the immunoregulatory roles of the glycocalyx in health and disease.
Insights
Sialic acid glycans on T cells regulate programmed cell death by suppressing Fas receptor activity. This finding highlights the role of the T cell glycocalyx in immune regulation and therapeutic potential.
Area of Science:
- Immunology
- Cell Biology
- Glycobiology
Background:
- T cells are key to adaptive immunity, with their persistence regulated by programmed cell death pathways.
- Tumor Necrosis Factor (TNF) receptor superfamily members mediate cell death, and their function can be modulated by sialoglycans.
- Sialoglycans on cell death receptors are known to attenuate apoptotic functions, acting as a pro-survival mechanism in cancer, but their role in T cells is unknown.
Purpose of the Study:
- To investigate the role of sialoglycans in regulating programmed cell death of human T cells.
- To explore the impact of sialoglycan deficiency on Fas receptor (FasR) activity and associated signaling pathways.
- To determine if sialoglycans are immunophysiological regulators of T cell death.
Main Methods:
- Utilized immortalized (Jurkat) and primary human T cells deficient in sialoglycans.
- Assessed apoptosis induced by Fas receptor (FasR), TNFR1, and TRAIL-R1.
- Analyzed FasR dynamic reorganization and employed phosphoproteomics to study signaling pathways.
- Used a sialic acid-cleaving enzyme (sialidase) on primary human T cells.
Main Results:
- T cell sialoglycans specifically suppressed Fas receptor-induced apoptosis, but not that of TNFR1 or TRAIL-R1.
- Sialoglycan deficiency increased FasR dynamic reorganization, indicating glycans limit receptor clustering.
- Loss of sialoglycans negatively regulated the pro-survival MAPK/ERK signaling pathway.
- Sialidase treatment confirmed sialoglycans as regulators of FasR-driven cell death in primary T cells.
Conclusions:
- Sialoglycans on T cells are critical regulators of Fas receptor-mediated programmed cell death.
- The T cell glycocalyx, specifically sialoglycans, influences cell fate decisions via the Fas pathway.
- These findings provide a basis for understanding the immunoregulatory roles of the glycocalyx and its therapeutic potential in T cell-based therapies.
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