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

Area of Science:

• Immunology
• Glycobiology
• Cell Biology

Background:

• T cells are crucial for adaptive immunity, with their persistence regulated by programmed cell death pathways.
• Tumor Necrosis Factor (TNF) receptor superfamily members mediate T cell death.
• α2-6-linked sialic acid-terminated glycans (sialoglycans) on death receptors can attenuate apoptosis, acting as a pro-survival mechanism in cancer.

Purpose of the Study:

• To investigate the unexplored role of sialoglycans in regulating cell death receptor activity on human T cells.
• To understand how T cell glycan editing could be therapeutically beneficial.

Main Methods:

• Utilized an immortalized T cell line (ST6GAL1^-/- Jurkat) lacking α2-6-sialoglycans.
• Assessed apoptosis induced by Fas receptor (FasR), TNFR1, and TRAIL-R1.
• Analyzed FasR reorganization and employed phosphoproteomics to study signaling pathways.
• Used a recombinant sialic acid-cleaving enzyme (sialidase) on primary human T cells.

Main Results:

• Loss of α2-6-sialoglycans attenuated FasR-induced apoptosis in Jurkat cells, with a lesser effect on TNFR1 and TRAIL-R1.
• FasR reorganization was limited in ST6GAL1^-/- Jurkat cells compared to wild-type.
• Phosphoproteomics indicated that sialoglycan loss negatively regulated the pro-survival MAPK/ERK pathway.
• Sialidase treatment confirmed sialoglycans regulate FasR-driven cell death in primary human T cells.

Conclusions:

• Sialoglycans on T cells significantly influence cell fate, particularly through the Fas receptor pathway.
• These findings underscore the immunoregulatory importance of the T cell glycocalyx in health and disease.
• Provides a basis for further research into therapeutic glycan editing of T cells.