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...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-02-01
|
Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC3930506?pdf=render |
id |
doaj-626b76e763964d4b96c17efc72bbb0ba |
---|---|
record_format |
Article |
spelling |
doaj-626b76e763964d4b96c17efc72bbb0ba2020-11-25T00:02:54ZengPublic 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.http://europepmc.org/articles/PMC3930506?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
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 |
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 |
title |
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_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_sort |
natural polymorphisms in tap2 influence negative selection and cd4∶cd8 lineage commitment in the rat. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2014-02-01 |
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. |
url |
http://europepmc.org/articles/PMC3930506?pdf=render |
work_keys_str_mv |
AT jonatantuncel naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT sabrinahaag naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT anthonycyyau naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT ulrikanorin naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT ameliebaud naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT eriklonnblom naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT kliomaratou naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT ajimmyytterberg naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT dianaekman naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT soleythordardottir naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT martinajohannesson naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT alangillett naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT euratransconsortium naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT pernillastridh naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT majajagodic naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT tomasolsson naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT albertofernandezteruel naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT romanazubarev naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT richardmott naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT timothyjaitman naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT jonathanflint naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat AT rikardholmdahl naturalpolymorphismsintap2influencenegativeselectionandcd4cd8lineagecommitmentintherat |
_version_ |
1725436029104553984 |