Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing

Mariana Borsa; Niculò Barandun; Fabienne Gräbnitz; Isabel Barnstorf; Nicolas S Baumann; Katharina Pallmer; Samira Baumann; Dominique Stark; Miroslav Balaz; Nathalie Oetiker; Franziska Wagen; Christian Wolfrum; Anna Katharina Simon; Nicole Joller; Yves Barral; Roman Spörri; Annette Oxenius

doi:10.1038/s41467-021-22954-y

Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing

Nat Commun. 2021 May 11;12(1):2715. doi: 10.1038/s41467-021-22954-y.

Authors

Mariana Borsa^{1

2}, Niculò Barandun^#¹, Fabienne Gräbnitz^#¹, Isabel Barnstorf¹, Nicolas S Baumann¹, Katharina Pallmer¹, Samira Baumann¹, Dominique Stark¹, Miroslav Balaz³, Nathalie Oetiker¹, Franziska Wagen¹, Christian Wolfrum³, Anna Katharina Simon², Nicole Joller⁴, Yves Barral⁵, Roman Spörri¹, Annette Oxenius⁶

Affiliations

¹ Institute of Microbiology, ETH Zürich, Zurich, Switzerland.
² Medical Sciences Division, NDORMS, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
³ Institute of Food Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
⁴ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
⁵ Institute of Biochemistry, ETH Zürich, Zurich, Switzerland.
⁶ Institute of Microbiology, ETH Zürich, Zurich, Switzerland. oxenius@microbio.ethz.ch.

^# Contributed equally.

Abstract

Efficient immune responses rely on heterogeneity, which in CD8⁺ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8⁺ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8⁺ T cells reveals that virtual memory cells (T_VM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8⁺ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics*
Aging / immunology
Animals
Asymmetric Cell Division / genetics*
Asymmetric Cell Division / immunology
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology*
Cell Proliferation / drug effects
Gene Expression Regulation
Immunity, Innate
Immunologic Memory / genetics*
Interferon-gamma / genetics
Interferon-gamma / immunology
Interleukin-1beta / genetics
Interleukin-1beta / immunology
Interleukin-2 Receptor beta Subunit / genetics
Interleukin-2 Receptor beta Subunit / immunology
Lectins, C-Type / genetics
Lectins, C-Type / immunology
Lymphocyte Activation
Mice
NK Cell Lectin-Like Receptor Subfamily K / genetics
NK Cell Lectin-Like Receptor Subfamily K / immunology
Receptors, CXCR3 / genetics
Receptors, CXCR3 / immunology
Receptors, Immunologic / genetics
Receptors, Immunologic / immunology
Receptors, Interleukin-7 / genetics
Receptors, Interleukin-7 / immunology
Signal Transduction
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / immunology

Substances

Cxcr3 protein, mouse
IL1B protein, mouse
Il2rb protein, mouse
Interleukin-1beta
Interleukin-2 Receptor beta Subunit
Klrg1 protein, mouse
Klrk1 protein, mouse
Lectins, C-Type
NK Cell Lectin-Like Receptor Subfamily K
Receptors, CXCR3
Receptors, Immunologic
Receptors, Interleukin-7
Interferon-gamma
mTOR protein, mouse
TOR Serine-Threonine Kinases
Sirolimus

Grants and funding

103830/Z/14/Z/WT_/Wellcome Trust/United Kingdom