Per citar aquest document: http://ddd.uab.cat/record/142701
Natural Polymorphisms in Tap2 Influence Negative Selection and CD4:CD8 Lineage Commitment in the Rat
Tuncel, Jonatan (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Haag, Sabrina (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Yau, Anthony C. (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Norin, Ulrika (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Baud, Amelie (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Lönnblom, Erik (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Maratou, Klio (Imperial College London)
Ytterberg, A. Jimmy (Karolinska University Hospital)
Ekman, Diana (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Thordardottir, Soley (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Johannesson, Martina (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Gillett, Alan (Karolinska University Hospital)
Stridh, Pernilla (Karolinska University Hospital)
Jagodic, Maja (Karolinska University Hospital)
Olsson, Tomas (Karolinska University Hospital)
Fernández-Teruel, Albert (Universitat Autònoma de Barcelona. Departament de Psiquiatria i Medicina Legal)
Zubarev, Roman A. (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
Mott, Richard (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Aitman, Timothy J. (Imperial College London)
Flint, Jonathan (Wellcome Trust Centre for Human Genetics (Oxford, Regne Unit))
Holmdahl, Rikard (Karolinska Institutet. Department of Medical Biochemistry and Biophysics)
EURATRANS Consortium

Data: 2014
Resum: 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.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: article ; recerca ; publishedVersion
Matèria: Major histocompatibility complex ; Cytotoxic T cells ; Antigen presentation ; MHC class I genes ; T cells ; Haplotypes ; Quantitative trait loci ; T helper cells
Publicat a: PLoS Genetics, Vol. 10 Issue 2 (February 2014) , p. e1004151, ISSN 1553-7390

DOI: 10.1371/journal.pgen.1004151


21 p, 2.1 MB

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