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 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.