title: The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells.
abstract: Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells. In this paper, we propose an even simpler explanation: that it results from the loss of T cells that have attained replicative senescence (i.e., the Hayflick limit). Stochastic numerical simulations of naive T cell population dynamics, based on experimental parameters, show that the rate of homeostatic T cell proliferation increases after the age of ∼60 y because naive T cells collectively approach replicative senescence. This leads to a sharp decline of effective clonal diversity after ∼70 y, in agreement with empirical data. A mathematical analysis predicts that, without an increase in the naive T cell proliferation rate, this decline will occur >50 yr later than empirically observed. These results are consistent with a model in which exhaustion of the proliferative capacity of naive T cells causes a sharp decline of their effective clonal diversity and imply that therapeutic potentiation of thymopoiesis might either prevent or reverse this outcome.
authors.affiliation: African Institute for Mathematical Sciences, Muizenberg 7945, Cape Town, South Africa; African Institute for Mathematical Sciences, Legon, Accra, Ghana; Stellenbosch University, Matieland 7602, Stellenbosch, South Africa; and wndifon@aims.ac.za.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Ndifon
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Jonathan
authors.identifier: 0000-0003-0506-4794
authors.initials: J
authors.lastname: Dushoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D049109:Cell Proliferation; D016922:Cellular Senescence; D002999:Clone Cells; D003198:Computer Simulation; D004261:DNA Replication; D006706:Homeostasis; D006801:Humans; D008213:Lymphocyte Activation; D008875:Middle Aged; D008954:Models, Biological; D013269:Stochastic Processes; D055815:Young Adult