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

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.