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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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Autores principales: Tuncel, Jonatan, Haag, Sabrina, Yau, Anthony C. Y., Norin, Ulrika, Baud, Amelie, Lönnblom, Erik, Maratou, Klio, Ytterberg, A. Jimmy, Ekman, Diana, Thordardottir, Soley, Johannesson, Martina, Gillett, Alan, Stridh, Pernilla, Jagodic, Maja, Olsson, Tomas, Fernández-Teruel, Alberto, Zubarev, Roman A., Mott, Richard, Aitman, Timothy J., Flint, Jonathan, Holmdahl, Rikard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930506/
https://www.ncbi.nlm.nih.gov/pubmed/24586191
http://dx.doi.org/10.1371/journal.pgen.1004151
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author Tuncel, Jonatan
Haag, Sabrina
Yau, Anthony C. Y.
Norin, Ulrika
Baud, Amelie
Lönnblom, Erik
Maratou, Klio
Ytterberg, A. Jimmy
Ekman, Diana
Thordardottir, Soley
Johannesson, Martina
Gillett, Alan
Stridh, Pernilla
Jagodic, Maja
Olsson, Tomas
Fernández-Teruel, Alberto
Zubarev, Roman A.
Mott, Richard
Aitman, Timothy J.
Flint, Jonathan
Holmdahl, Rikard
author_facet Tuncel, Jonatan
Haag, Sabrina
Yau, Anthony C. Y.
Norin, Ulrika
Baud, Amelie
Lönnblom, Erik
Maratou, Klio
Ytterberg, A. Jimmy
Ekman, Diana
Thordardottir, Soley
Johannesson, Martina
Gillett, Alan
Stridh, Pernilla
Jagodic, Maja
Olsson, Tomas
Fernández-Teruel, Alberto
Zubarev, Roman A.
Mott, Richard
Aitman, Timothy J.
Flint, Jonathan
Holmdahl, Rikard
author_sort Tuncel, Jonatan
collection PubMed
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.
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spelling pubmed-39305062014-02-25 Natural Polymorphisms in Tap2 Influence Negative Selection and CD4∶CD8 Lineage Commitment in the Rat Tuncel, Jonatan Haag, Sabrina Yau, Anthony C. Y. Norin, Ulrika Baud, Amelie Lönnblom, Erik Maratou, Klio Ytterberg, A. Jimmy Ekman, Diana Thordardottir, Soley Johannesson, Martina Gillett, Alan Stridh, Pernilla Jagodic, Maja Olsson, Tomas Fernández-Teruel, Alberto Zubarev, Roman A. Mott, Richard Aitman, Timothy J. Flint, Jonathan Holmdahl, Rikard PLoS Genet Research Article 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. Public Library of Science 2014-02-20 /pmc/articles/PMC3930506/ /pubmed/24586191 http://dx.doi.org/10.1371/journal.pgen.1004151 Text en © 2014 Tuncel et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tuncel, Jonatan
Haag, Sabrina
Yau, Anthony C. Y.
Norin, Ulrika
Baud, Amelie
Lönnblom, Erik
Maratou, Klio
Ytterberg, A. Jimmy
Ekman, Diana
Thordardottir, Soley
Johannesson, Martina
Gillett, Alan
Stridh, Pernilla
Jagodic, Maja
Olsson, Tomas
Fernández-Teruel, Alberto
Zubarev, Roman A.
Mott, Richard
Aitman, Timothy J.
Flint, Jonathan
Holmdahl, Rikard
Natural Polymorphisms in Tap2 Influence Negative Selection and CD4∶CD8 Lineage Commitment in the Rat
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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930506/
https://www.ncbi.nlm.nih.gov/pubmed/24586191
http://dx.doi.org/10.1371/journal.pgen.1004151
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