Institute for Infection and Immunity, St. George’s, University of London, London SW17 0RE, UK
Kelly L. Miners
Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
Julio Lahoz-Beneytez
Department of Infectious Disease, Imperial College London, London W2 1PG, UK
Rhiannon E. Jones
Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
Laureline Roger
Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
Christina Baboonian
Institute for Infection and Immunity, St. George’s, University of London, London SW17 0RE, UK
Yan Zhang
Institute for Infection and Immunity, St. George’s, University of London, London SW17 0RE, UK
Eddie C.Y. Wang
Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
Marc K. Hellerstein
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA
Joseph M. McCune
HIV Frontiers Program, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation, Seattle, WA 98109, USA
Duncan M. Baird
Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
David A. Price
Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; Corresponding author
Derek C. Macallan
Institute for Infection and Immunity, St. George’s, University of London, London SW17 0RE, UK; St George’s University Hospitals NHS Foundation Trust, London SW17 0QT, UK; Corresponding author
Becca Asquith
Department of Infectious Disease, Imperial College London, London W2 1PG, UK; Corresponding author
Kristin Ladell
Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; Neonatal Unit, Singleton Hospital, Swansea Bay University Health Board, Swansea SA2 8QA, UK; Corresponding author
Summary: A central paradigm in the field of lymphocyte biology asserts that replicatively senescent memory T cells express the carbohydrate epitope CD57. These cells nonetheless accumulate with age and expand numerically in response to persistent antigenic stimulation. Here, we use in vivo deuterium labeling and ex vivo analyses of telomere length, telomerase activity, and intracellular expression of the cell-cycle marker Ki67 to distinguish between two non-exclusive scenarios: (1) CD57+ memory T cells do not proliferate and instead arise via phenotypic transition from the CD57− memory T cell pool; and/or (2) CD57+ memory T cells self-renew via intracompartmental proliferation. Our results provide compelling evidence in favor of the latter scenario and further suggest in conjunction with mathematical modeling that self-renewal is by far the most abundant source of newly generated CD57+ memory T cells. Immunological memory therefore appears to be intrinsically sustainable among highly differentiated subsets of T cells that express CD57.
