Asymmetric cell division safeguards memory CD8 T cell development
Fabienne Gräbnitz,
Dominique Stark,
Danielle Shlesinger,
Anthony Petkidis,
Mariana Borsa,
Alexander Yermanos,
Andreas Carr,
Niculò Barandun,
Arne Wehling,
Miroslav Balaz,
Timm Schroeder,
Annette Oxenius
Affiliations
Fabienne Gräbnitz
Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
Dominique Stark
Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
Danielle Shlesinger
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
Anthony Petkidis
Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Mariana Borsa
Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland; The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
Alexander Yermanos
Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
Andreas Carr
Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
Niculò Barandun
Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
Arne Wehling
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
Miroslav Balaz
Department of Metabolic Disease Research, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia; Department of Health Sciences and Technology, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland
Timm Schroeder
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
Annette Oxenius
Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland; Corresponding author
Summary: The strength of T cell receptor (TCR) stimulation and asymmetric distribution of fate determinants are both implied to affect T cell differentiation. Here, we uncover asymmetric cell division (ACD) as a safeguard mechanism for memory CD8 T cell generation specifically upon strong TCR stimulation. Using live imaging approaches, we find that strong TCR stimulation induces elevated ACD rates, and subsequent single-cell-derived colonies comprise both effector and memory precursor cells. The abundance of memory precursor cells emerging from a single activated T cell positively correlates with first mitosis ACD. Accordingly, preventing ACD by inhibition of protein kinase Cζ (PKCζ) during the first mitosis upon strong TCR stimulation markedly curtails the formation of memory precursor cells. Conversely, no effect of ACD on fate commitment is observed upon weak TCR stimulation. Our data provide relevant mechanistic insights into the role of ACD for CD8 T cell fate regulation upon different activation conditions.
