Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat

Autor: Tuncel, J., Haag, S., Yau, A.C., Norin, U., Baud, A., Lönnblom, E., Maratou, K., Ytterberg, A.J., Ekman, D., Thordardottir, S., Johannesson, M., Gillett, A., Stridh, P., Jagodic, M., Olsson, T., Fernández-Teruel, A., Zubarev, R.A., Mott, R., Aitman, T.J., Flint, J., Holmdahl, R.
Rok vydání: 2015
Předmět:
CD4-Positive T-Lymphocytes
Cancer Research
Quantitative trait loci
lcsh:QH426-470
Immune Cells
Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]
Major histocompatibility complex
T cells
MHC class I genes
chemical and pharmacologic phenomena
Cytotoxic T cells
CD8-Positive T-Lymphocytes
Biology
Major Histocompatibility Complex
Negative selection
T helper cells
ATP Binding Cassette Transporter
Subfamily B
Member 3
Histocompatibility Antigens
MHC class I
Genetics
Animals
Cytotoxic T cell
Cell Lineage
Selection
Genetic
Antigen presentation
Molecular Biology
GeneralLiterature_REFERENCE(e.g.
dictionaries
encyclopedias
glossaries)
Alleles
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
Recombination
Genetic
Antigen Presentation
MHC Class I Gene
Cell Differentiation
Transporter associated with antigen processing
Rats
lcsh:Genetics
Gene Expression Regulation
Haplotypes
Immune System
T cell selection
biology.protein
Medicine
Clinical Immunology
ATP-Binding Cassette Transporters
CD8
Research Article
Zdroj: Plos Genetics, 10, e1004151
Plos Genetics, 10, 2, pp. e1004151
Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
PLoS Genetics
Tuncel, J, Haag, S, Yau, A C Y, Norin, U, Baud, A, Lönnblom, E, Maratou, K, Ytterberg, A J, Ekman, D, Thordardottir, S, Johannesson, M, Gillett, A, Stridh, P, Jagodic, M, Olsson, T, Fernández-Teruel, A, Zubarev, R A, Mott, R, Aitman, T J, Flint, J, Holmdahl, R 2014, ' Natural Polymorphisms in Tap2 Influence Negative Selection and CD4 : CD8 Lineage Commitment in the Rat ', PLoS Genetics, vol. 10, no. 2, e1004151 . https://doi.org/10.1371/journal.pgen.1004151
PLoS Genetics, Vol 10, Iss 2, p e1004151 (2014)
ISSN: 1553-7404
DOI: 10.1371/journal.pgen.1004151
Popis: 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.
Author Summary Peptides from degraded cytoplasmic proteins are transported via TAP into the endoplasmic reticulum for loading onto MHC class I molecules. TAP is encoded by Tap1 and Tap2, which in rodents are located close to the MHC class I genes. In the rat, genetic variation in Tap2 gives rise to two different transporters: a promiscuous A variant (TAP-A) and a more restrictive B variant (TAP-B). It has been proposed that the class I molecule in the DA rat (RT1-Aa) has co-evolved with TAP-A and it has been shown that RT1-Aa antigenicity is changed when co-expressed with TAP-B. To study the contribution of different allelic combinations of RT1-A and Tap2 to the variation in MHC expression and T cell selection, we generated DA rats with either congenic or background alleles in the RT1-A and Tap2 loci. We found increased numbers of mature CD8SP cells in the thymus of rats which co-expressed RT1-Aa and TAP-B. This increase of CD8 cells could be explained by reduced negative selection, but did not correlate with RT1-Aa expression levels on thymic antigen presenting cells. Thus, our results identify a crucial role of the TAP and the quality of the MHC class I repertoire in regulating T cell selection.
Databáze: OpenAIRE
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