Abstract
BackgroundRegulatory T cells (Tregs) play an essential role in the control of the immune response. Treg cells represent important targets for therapeutic interventions of the immune system. Therefore, it will be very important to understand in more detail which genes are specifically activated in Treg cells versus T helper (Th) cells, and which gene regulatory circuits may be involved in specifying and maintaining Treg cell homeostasis.ResultsWe isolated Treg and Th cells from a genetically diverse family of 31 BXD type recombinant inbred strains and the fully inbred parental strains of this family--C57BL/6J and DBA/2J. Subsequently genome-wide gene expression studies were performed from the isolated Treg and Th cells. A comparative analysis of the transcriptomes of these cell populations allowed us to identify many novel differentially expressed genes. Analysis of cis- and trans-expression Quantitative Trait Loci (eQTLs) highlighted common and unique regulatory mechanisms that are active in the two cell types. Trans-eQTL regions were found for the Treg functional genes Nrp1, Stat3 and Ikzf4. Analyses of the respective QTL intervals suggested several candidate genes that may be involved in regulating these genes in Treg cells. Similarly, possible candidate genes were found which may regulate the expression of F2rl1, Ctla4, Klrb1f. In addition, we identified a focused group of candidate genes that may be important for the maintenance of self-tolerance and the prevention of allergy.ConclusionsVariation of expression across the strains allowed us to find many novel gene-interaction networks in both T cell subsets. In addition, these two data sets enabled us to identify many differentially expressed genes and to nominate candidate genes that may have important functions for the maintenance of self-tolerance and the prevention of allergy.
Highlights
Regulatory T cells (Tregs) play an essential role in the control of the immune response
To better understand gene variants that underlie disease predispositions related to T regulatory (Treg) functions and to identify regulatory networks related to both Treg and T helper (Th) cells, we undertook a systems genetics analysis of gene expression in these cell types using a genetic reference panel consisting of 31 members of the large BXD family of recombinant inbred strains [13,14]
CD4+CD25+ T regulatory (Treg) cells and CD4+CD25T helper (Th) cells were isolated from the spleens of 31 BXD strains and the parental strains DBA/2J and C57BL/6J by fluorescence activated cell sorting
Summary
Regulatory T cells (Tregs) play an essential role in the control of the immune response. To better understand gene variants that underlie disease predispositions related to Treg functions and to identify regulatory networks related to both Treg and Th cells, we undertook a systems genetics analysis of gene expression in these cell types using a genetic reference panel consisting of 31 members of the large BXD family of recombinant inbred strains [13,14]. The high level of genetic variation among BXD strains can be exploited to systematically study the genetic control of gene expression even at the level of single cell types [16] and even higher order genotype-tophenotype relations, including for example global analysis of disease susceptibility [17,18,19]
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