title: Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice.
abstract: Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment.
authors.affiliation: Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Thea
authors.initials: T
authors.lastname: Hogan
authors.affiliation: Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Gossel
authors.affiliation: Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom andrew.yates@glasgow.ac.uk benedict.seddon@ucl.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Yates
authors.affiliation: Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; andrew.yates@glasgow.ac.uk benedict.seddon@ucl.ac.uk.
authors.forename: Benedict
authors.initials: B
authors.lastname: Seddon
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage; D005434:Flow Cytometry; D008297:Male; D008954:Models, Biological
keywords: Ki67; T-cell homeostasis; kinetic heterogeneity; mathematical modeling