title: Insights into immune system development and function from mouse T-cell repertoires.
abstract: The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors. This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts on the surface receptor gene each time a new immune cell is created from a stem cell. By analyzing T-cell receptor (TCR) sequence repertoires taken from the blood and thymus of mice of different ages, we quantify the changes in the VDJ recombination process that occur from embryo to young adult. We find a rapid increase with age in the number of random insertions and a dramatic increase in diversity. Because the blood accumulates thymic output over time, blood repertoires are mixtures of different statistical recombination processes, and we unravel the mixture statistics to obtain a picture of the time evolution of the early immune system. Sequence repertoire analysis also allows us to detect the statistical impact of selection on the output of the VDJ recombination process. The effects we find are nearly identical between thymus and blood, suggesting that our analysis mainly detects selection for proper folding of the TCR receptor protein. We further find that selection is weaker in laboratory mice than in humans and it does not affect the diversity of the repertoire.
authors.affiliation: Joseph Henry Laboratories, Princeton University, Princeton, NJ 08544.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Sethna
authors.affiliation: Joseph Henry Laboratories, Princeton University, Princeton, NJ 08544.|Laboratoire de Physique Théorique, UMR8549, CNRS, École Normale Supérieure, 75005 Paris, France.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Elhanati
authors.affiliation: Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903.
authors.forename: Crissy S
authors.initials: CS
authors.lastname: Dudgeon
authors.affiliation: Joseph Henry Laboratories, Princeton University, Princeton, NJ 08544; ccallan@princeton.edu.
authors.forename: Curtis G
authors.initials: CG
authors.lastname: Callan
authors.affiliation: Institute for Advanced Study, Princeton NJ 08540.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Laboratoire de Physique Statistique, UMR8550, CNRS, École Normale Supérieure, 75005 Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Mora
authors.affiliation: Laboratoire de Physique Théorique, UMR8549, CNRS, École Normale Supérieure, 75005 Paris, France.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Walczak
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000375:Aging; D000818:Animals; D014644:Genetic Variation / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D060152:V(D)J Recombination / Q000235:genetics / Q000276:immunology; D050441:VDJ Exons / Q000235:genetics / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell
keywords: T cells; VDJ recombination; immunology; mouse; sequencing