Format

Send to

Choose Destination
PLoS Genet. 2014 Feb 20;10(2):e1004151. doi: 10.1371/journal.pgen.1004151. eCollection 2014 Feb.

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

Author information

1
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
2
Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
3
Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
4
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden ; Medical Proteomics, Department of Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden and Science for Life Laboratory, Solna, Sweden.
5
Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
6
Medical Psychology Unit, Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain.
7
Medical Proteomics, Department of Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden and Science for Life Laboratory, Solna, Sweden.

Abstract

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.

PMID:
24586191
PMCID:
PMC3930506
DOI:
10.1371/journal.pgen.1004151
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center