title: Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction.
abstract: Every person carries a vast repertoire of CD4+ T-helper cells and CD8+ cytotoxic T cells for a healthy immune system. Somatic VDJ recombination at genomic loci that encode the T-cell receptor (TCR) is a key step during T-cell development, but how a single T cell commits to become either CD4+ or CD8+ is poorly understood. To evaluate the influence of TCR sequence variation on CD4+/CD8+ lineage commitment, we sequenced rearranged TCRs for both α and β chains in naïve T cells isolated from healthy donors and investigated gene segment usage and recombination patterns in CD4+ and CD8+ T-cell subsets. Our data demonstrate that most V and J gene segments are strongly biased in the naïve CD4+ and CD8+ subsets with some segments increasing the odds of being CD4+ (or CD8+) up to five-fold. These V and J gene associations are highly reproducible across individuals and independent of classical HLA genotype, explaining ~11% of the observed variance in the CD4+ vs. CD8+ propensity. In addition, we identified a strong independent association of the electrostatic charge of the complementarity determining region 3 (CDR3) in both α and β chains, where a positively charged CDR3 is associated with CD4+ lineage and a negatively charged CDR3 with CD8+ lineage. Our findings suggest that somatic variation in different parts of the TCR influences T-cell lineage commitment in a predominantly additive fashion. This notion can help delineate how certain structural features of the TCR-peptide-HLA complex influence thymic selection.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America; Department of Clinical Immunology and Rheumatology, Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Klarenbeek
authors.affiliation: Department of Clinical Immunology and Rheumatology, Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marieke E
authors.initials: ME
authors.lastname: Doorenspleet
authors.affiliation: Department of Clinical Immunology and Rheumatology, Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rebecca E E
authors.initials: RE
authors.lastname: Esveldt
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Barbera D C
authors.initials: BD
authors.lastname: van Schaik
authors.affiliation: Department of Immunogenetics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.
authors.forename: Neubury
authors.initials: N
authors.lastname: Lardy
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Antoine H C
authors.initials: AH
authors.lastname: van Kampen
authors.affiliation: Department of Clinical Immunology and Rheumatology, Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.affiliation: Laboratory for Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America; Department of Epidemiology, University Medical Center, Utrecht, The Netherlands; Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Department of Clinical Immunology and Rheumatology, Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: de Vries
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D019672:Genes, T-Cell Receptor / Q000235:genetics*; D019673:Genes, T-Cell Receptor alpha / Q000235:genetics; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D014644:Genetic Variation; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
chemical_list: D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell