Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat.
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 cel...
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Public Library of Science (PLoS)
2014-02-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1004151 |
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| author | Jonatan Tuncel Sabrina Haag Anthony C Y Yau Ulrika Norin Amelie Baud Erik Lönnblom Klio Maratou A Jimmy Ytterberg Diana Ekman Soley Thordardottir Martina Johannesson Alan Gillett EURATRANS Consortium Pernilla Stridh Maja Jagodic Tomas Olsson Alberto Fernández-Teruel Roman A Zubarev Richard Mott Timothy J Aitman Jonathan Flint Rikard Holmdahl |
| author_facet | Jonatan Tuncel Sabrina Haag Anthony C Y Yau Ulrika Norin Amelie Baud Erik Lönnblom Klio Maratou A Jimmy Ytterberg Diana Ekman Soley Thordardottir Martina Johannesson Alan Gillett EURATRANS Consortium Pernilla Stridh Maja Jagodic Tomas Olsson Alberto Fernández-Teruel Roman A Zubarev Richard Mott Timothy J Aitman Jonathan Flint Rikard Holmdahl |
| author_sort | Jonatan Tuncel |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-626b76e763964d4b96c17efc72bbb0ba |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2014-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-626b76e763964d4b96c17efc72bbb0ba2025-08-20T02:34:07ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-02-01102e100415110.1371/journal.pgen.1004151Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat.Jonatan TuncelSabrina HaagAnthony C Y YauUlrika NorinAmelie BaudErik LönnblomKlio MaratouA Jimmy YtterbergDiana EkmanSoley ThordardottirMartina JohannessonAlan GillettEURATRANS ConsortiumPernilla StridhMaja JagodicTomas OlssonAlberto Fernández-TeruelRoman A ZubarevRichard MottTimothy J AitmanJonathan FlintRikard HolmdahlGenetic 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.https://doi.org/10.1371/journal.pgen.1004151 |
| spellingShingle | Jonatan Tuncel Sabrina Haag Anthony C Y Yau Ulrika Norin Amelie Baud Erik Lönnblom Klio Maratou A Jimmy Ytterberg Diana Ekman Soley Thordardottir Martina Johannesson Alan Gillett EURATRANS Consortium Pernilla Stridh Maja Jagodic Tomas Olsson Alberto Fernández-Teruel Roman A Zubarev Richard Mott Timothy J Aitman Jonathan Flint Rikard Holmdahl Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat. PLoS Genetics |
| title | Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat. |
| title_full | Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat. |
| title_fullStr | Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat. |
| title_full_unstemmed | Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat. |
| title_short | Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat. |
| title_sort | natural polymorphisms in tap2 influence negative selection and cd4∶cd8 lineage commitment in the rat |
| url | https://doi.org/10.1371/journal.pgen.1004151 |
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