FAS-controlled T cells drive lymphoproliferation through glycolysis without effector differentiation

Maccari ME, König C, Andrieux G, Kury P, Berger SA, Mann J, Kelly B, Völkl S, Huang C, Helmstädter M, Lagies S, Fischer M, Baixauli F, Gorka O, Groß O, Hufnagel M, Salou S, Farmand S, Heine S, Schuster V, Willenbacher W, Dückers G, Grimbacher B, Warnatz K, Kapp FG, Lorenz M, Groß M, Wittner J, Elling R, Scorrano L, Koenig IA, Bengsch B, Speckmann C, Kammerer B, Börries M, Schwarz K, Hertel J, Pearce EL, Ehl S, Klein Geltink RI, Rensing-Ehl A (2026)

Publication Type: Journal article

Publication year: 2026

Book Volume: 2

Article Number: e20250233

Journal Issue: 4

DOI: 10.70962/jhi.20250233

Abstract

Lymphoproliferation in autoimmune lymphoproliferative syndrome (ALPS) due to FAS deficiency is driven by highly proliferative FAS-controlled T cells (FCT) with a distinct molecular signature. Activating signals and metabolic fuels of their proliferation are poorly understood. Lymphoproliferation caused by proliferative T cells is also a hallmark of acute EBV infection. In these antiviral T cells, a metabolic switch to glycolysis underpins effector differentiation and IFNγ translation. Here, we used EBV-induced CD8 effector T cells as a benchmark to characterize FCT metabolism. Metabolic assays, RNA sequencing, and in silico computational analysis revealed that FCT are as highly glycolytic as EBV-induced effector T cells, but this metabolic program is uncoupled from T-BET expression and IFNγ production. In contrast to virus-activated T cells, FCT showed mitochondrial hyperpolarization and elevated reactive oxygen species production. These findings support a model of FCT lymphoproliferation, in which activating signals strongly enhance glycolysis but do not induce classical effector differentiation.

Authors with CRIS profile

Simon Völkl Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Johns Hopkins Hospital US United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Venetian Institute of Molecular Medicine (VIMM) IT Italy (IT) State University of New York Upstate Medical University (SUNY) US United States (USA) (US) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Medizinische Universität Innsbruck AT Austria (AT) Helios Klinikum Krefeld DE Germany (DE) Universität Ulm DE Germany (DE) Universität Basel CH Switzerland (CH) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald DE Germany (DE) BC Children's Hospital Research Institute CA Canada (CA)

How to cite

APA:

Maccari, M.E., König, C., Andrieux, G., Kury, P., Berger, S.A., Mann, J.,... Rensing-Ehl, A. (2026). FAS-controlled T cells drive lymphoproliferation through glycolysis without effector differentiation. , 2(4). https://doi.org/10.70962/jhi.20250233

MLA:

Maccari, Maria Elena, et al. "FAS-controlled T cells drive lymphoproliferation through glycolysis without effector differentiation." 2.4 (2026).

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