TY - JOUR
T1 - Natural Polymorphisms in Tap2 Influence Negative Selection and CD4:CD8 Lineage Commitment in the Rat
AU - Tuncel, Jonatan
AU - Haag, Sabrina
AU - Yau, Anthony C.Y.
AU - Norin, Ulrika
AU - Baud, Amelie
AU - Lönnblom, Erik
AU - Maratou, Klio
AU - Ytterberg, A. Jimmy
AU - Ekman, Diana
AU - Thordardottir, Soley
AU - Johannesson, Martina
AU - Gillett, Alan
AU - Stridh, Pernilla
AU - Jagodic, Maja
AU - Olsson, Tomas
AU - Fernández-Teruel, Alberto
AU - Zubarev, Roman A.
AU - Mott, Richard
AU - Aitman, Timothy J.
AU - Flint, Jonathan
AU - Holmdahl, Rikard
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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. © 2014 Tuncel et al.
AB - 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. © 2014 Tuncel et al.
UR - https://ddd.uab.cat/record/142701
U2 - https://doi.org/10.1371/journal.pgen.1004151
DO - https://doi.org/10.1371/journal.pgen.1004151
M3 - Article
VL - 10
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
M1 - e1004151
ER -