Coordinated ARP2/3 and glycolytic activities regulate the morphological and functional fitness of human CD8+ T cells
Anton Kamnev,
Tanvi Mehta,
Matthias Wielscher,
Beatriz Chaves,
Claire Lacouture,
Anna-Katharina Mautner,
Lisa E. Shaw,
Michael Caldera,
Jörg Menche,
Wolfgang P. Weninger,
Matthias Farlik,
Kaan Boztug,
Loïc Dupré
Affiliations
Anton Kamnev
Department of Dermatology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
Tanvi Mehta
Department of Dermatology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
Matthias Wielscher
Department of Dermatology, Medical University of Vienna, Vienna, Austria
Beatriz Chaves
Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil; Computational Modeling Group, Oswaldo Cruz Foundation (Fiocruz), Eusébio, Brazil
Claire Lacouture
Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
Anna-Katharina Mautner
Department of Dermatology, Medical University of Vienna, Vienna, Austria
Lisa E. Shaw
Department of Dermatology, Medical University of Vienna, Vienna, Austria
Michael Caldera
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Jörg Menche
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Max Perutz Labs, University of Vienna, Vienna, Austria
Wolfgang P. Weninger
Department of Dermatology, Medical University of Vienna, Vienna, Austria
Matthias Farlik
Department of Dermatology, Medical University of Vienna, Vienna, Austria
Kaan Boztug
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
Loïc Dupré
Department of Dermatology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria; Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Corresponding author
Summary: Actin cytoskeleton remodeling sustains the ability of cytotoxic T cells to search for target cells and eliminate them. We here investigated the relationship between energetic status, actin remodeling, and functional fitness in human CD8+ effector T cells. Cell spreading during migration or immunological synapse assembly mirrored cytotoxic activity. Morphological and functional fitness were boosted by interleukin-2 (IL-2), which also stimulated the transcription of glycolytic enzymes, actin isoforms, and actin-related protein (ARP)2/3 complex subunits. This molecular program scaled with F-actin content and cell spreading. Inhibiting glycolysis impaired F-actin remodeling at the lamellipodium, chemokine-driven motility, and adhesion, while mitochondrial oxidative phosphorylation blockade impacted cell elongation during confined migration. The severe morphological and functional defects of ARPC1B-deficient T cells were only partially corrected by IL-2, emphasizing ARP2/3-mediated actin polymerization as a crucial energy state integrator. The study therefore underscores the tight coordination between metabolic and actin remodeling programs to sustain the cytotoxic activity of CD8+ T cells.
