title: Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells.
abstract: The adaptive immune system's capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, the influence of individual genetic and epigenetic differences on these repertoires is not typically measured. By leveraging the unique characteristics of B, CD4(+) T and CD8(+) T-lymphocyte subsets from monozygotic twins, we quantify the impact of heritable factors on both the V(D)J recombination process and on thymic selection. We show that the resulting biases in both V(D)J usage and N/P addition lengths, which are found in naïve and antigen experienced cells, contribute to significant variation in the CDR3 region. Moreover, we show that the relative usage of V and J gene segments is chromosomally biased, with ∼1.5 times as many rearrangements originating from a single chromosome. These data refine our understanding of the heritable mechanisms affecting the repertoire, and show that biases are evident on a chromosome-wide level.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Rubelt
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Bolen
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Helen M
authors.identifier: http://orcid.org/0000-0003-2047-6543
authors.initials: HM
authors.lastname: McGuire
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Deaptment of Computational Biology &Bioinformatics, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Vander Heiden
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Deaptment of Computational Biology &Bioinformatics, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gadala-Maria
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Levin
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Palo Alto, California 94304, USA.
authors.forename: Ghia M
authors.initials: GM
authors.lastname: Euskirchen
authors.affiliation: Program in Immunology, Department of Microbiology and Immunology, Stanford University, Stanford, California 94305, USA.
authors.forename: Murad R
authors.initials: MR
authors.lastname: Mamedov
authors.affiliation: Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California 94304, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.affiliation: Department of Pediatrics (Infectious Diseases), Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Dekker
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Lindsay G
authors.initials: LG
authors.lastname: Cowell
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Deaptment of Computational Biology &Bioinformatics, Yale University, New Haven, Connecticut 06520, USA.|Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA.|Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Institute of Immunity, Department of Microbiology and Immunology, Transplantation and Infection, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D005803:Genes, Immunoglobulin / Q000235:genetics*; D019672:Genes, T-Cell Receptor / Q000235:genetics*; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014430:Twins, Monozygotic / Q000235:genetics*; D060152:V(D)J Recombination / Q000235:genetics*