title: Diversity and clonal selection in the human T-cell repertoire.
abstract: T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.
authors.affiliation: Divisions of Immunology and Rheumatology, Department of Medicine and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Stanford Center for Biomedical Informatics Research, and Departments of Pathology.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genetics, and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Departments of Pathology, Immunology, Stanford University, Stanford, CA 94305; and.
authors.forename: Jacob
authors.initials: J
authors.lastname: Glanville
authors.affiliation: Divisions of Immunology and Rheumatology, Department of Medicine and.
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Departments of Pathology.
authors.forename: Ji-Yeun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Biostatistics.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Olshen
authors.affiliation: Divisions of Immunology and Rheumatology, Department of Medicine and Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA 94306.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.affiliation: Departments of Pathology.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Boyd
authors.affiliation: Divisions of Immunology and Rheumatology, Department of Medicine and Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA 94306 jgoronzy@stanford.edu.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002451:Cell Compartmentation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
chemical_list: D022801:Complementarity Determining Regions; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell
keywords: T-cell homeostasis; adaptive immune responses; aging; immunosenescence