title: Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat.
abstract: Genetic variation in the major histocompatibility complex (MHC) affects CD4∶CD8 lineage commitment and MHC expression. However, the contribution of specific genes in this gene-dense region has not yet been resolved. Nor has it been established whether the same genes regulate MHC expression and T cell selection. Here, we assessed the impact of natural genetic variation on MHC expression and CD4∶CD8 lineage commitment using two genetic models in the rat. First, we mapped Quantitative Trait Loci (QTLs) associated with variation in MHC class I and II protein expression and the CD4∶CD8 T cell ratio in outbred Heterogeneous Stock rats. We identified 10 QTLs across the genome and found that QTLs for the individual traits colocalized within a region spanning the MHC. To identify the genes underlying these overlapping QTLs, we generated a large panel of MHC-recombinant congenic strains, and refined the QTLs to two adjacent intervals of ∼0.25 Mb in the MHC-I and II regions, respectively. An interaction between these intervals affected MHC class I expression as well as negative selection and lineage commitment of CD8 single-positive (SP) thymocytes. We mapped this effect to the transporter associated with antigen processing 2 (Tap2) in the MHC-II region and the classical MHC class I gene(s) (RT1-A) in the MHC-I region. This interaction was revealed by a recombination between RT1-A and Tap2, which occurred in 0.2% of the rats. Variants of Tap2 have previously been shown to influence the antigenicity of MHC class I molecules by altering the MHC class I ligandome. Our results show that a restricted peptide repertoire on MHC class I molecules leads to reduced negative selection of CD8SP cells. To our knowledge, this is the first study showing how a recombination between natural alleles of genes in the MHC influences lineage commitment of T cells.
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Tuncel
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Haag
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anthony C Y
authors.initials: AC
authors.lastname: Yau
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Norin
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Amelie
authors.initials: A
authors.lastname: Baud
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Lönnblom
authors.affiliation: Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Klio
authors.initials: K
authors.lastname: Maratou
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden ; Medical Proteomics, Department of Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden and Science for Life Laboratory, Solna, Sweden.
authors.forename: A Jimmy
authors.initials: AJ
authors.lastname: Ytterberg
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Diana
authors.initials: D
authors.lastname: Ekman
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Soley
authors.initials: S
authors.lastname: Thordardottir
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Johannesson
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Alan
authors.initials: A
authors.lastname: Gillett
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Stridh
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Medical Psychology Unit, Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernández-Teruel
authors.affiliation: Medical Proteomics, Department of Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden and Science for Life Laboratory, Solna, Sweden.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zubarev
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Mott
authors.affiliation: Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.affiliation: Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage; D005786:Gene Expression Regulation; D006649:Histocompatibility Antigens / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology; D051381:Rats; D011995:Recombination, Genetic; D012641:Selection, Genetic
chemical_list: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D006649:Histocompatibility Antigens; C038353:histocompatibility antigens RT, rat; C071692:TAP2 protein, human