Glycolytic flux sustains human Th1 identity and effector function via STAT1 glycosylation

Abir AH, Benz J, Frey B, Bruns H, Krönke G, Gaipl U, Schober K, Mougiakakos D, Mielenz D (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Life Science Alliance Life Science Alliance

Book Volume: 9

Journal Issue: 1

DOI: 10.26508/lsa.202503315

Abstract

T helper (Th) cell lineages are linked to metabolism, but precise mechanisms in human Th1 cells remain unclear. We addressed this question by in vitro stimulation and CRISPR/Cas9-mediated gene editing. Metabolic profiling revealed enhanced glycolytic activity in Th1 versus non-polarized cells, evidenced by increased extracellular acidification rate, ATP production via glycolysis, lactate secretion, NADH abundance, and elevated glycolysis-dependent anabolic activity. Inhibition of glycolysis reduced IFNγ production and STAT1 phosphorylation independent of JAK1/2 or SHP2 activity and STAT1 abundance, implicating glycolysis directly in sustaining STAT1-mediated Th1 functionality. O-glycosylation of STAT1 via O-glycosyltransferase was pivotal in modulating STAT1 activity. Pharmaceutical O-glycosyltransfer-ase inhibition prevented Th1 differentiation as well as STAT1 O-glycosylation. CRISPR/Cas9 mediated mutation of the O-glycosylation Ser499 and Thr510 sites diminished STAT1 Ser727 phosphorylation and IFNγ synthesis. Together, this study highlights glycolysis as key regulator of human Th1 cell identity and effector function, with STAT1 O-glycosylation selectively maintaining Th1 effector capacity. This mechanism could be explored to safeguard Th1 cells.

Authors with CRIS profile

Benjamin Frey Department of Radiation Oncology Heiko Bruns Department of Medicine 5 – Haematology and Oncology Udo Gaipl Department of Radiation Oncology

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE) Otto-von-Guericke-Universität Magdeburg DE Germany (DE)

How to cite

APA:

Abir, A.H., Benz, J., Frey, B., Bruns, H., Krönke, G., Gaipl, U.,... Mielenz, D. (2026). Glycolytic flux sustains human Th1 identity and effector function via STAT1 glycosylation. Life Science Alliance, 9(1). https://doi.org/10.26508/lsa.202503315

MLA:

Abir, Ariful Haque, et al. "Glycolytic flux sustains human Th1 identity and effector function via STAT1 glycosylation." Life Science Alliance 9.1 (2026).

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