The meta-Treg signature generated in silico is centered on IL-2, members of the TNF receptor superfamily and the endogenous opioid pathway

Regulatory T cells (Treg) are crucial in the proper balance of the immune system. A better knowledge of Treg-specific genes will extend our knowledge on their complex biology. However, to date there is no consensual Treg signature in the literature. Here, we extracted a list of 72 genes differentially expressed in Treg compared to CD4+ conventional T cells across 6 different but comparable publicly available datasets. A simple network analysis confirms that Foxp3 was a central node of the meta-Treg signature. A third of the genes from this in silico-generated signature interacted with IL-2, confirming the central role for this cytokine in Treg biology and the validity of our approach. When projected into a quantitative gene expression database, many genes of the meta-Treg signature were also expressed by other immune and non-immune cell subsets, with the noticeable exceptions of Foxp3, Ctla4, Tnfrsf4 and Tnfrsf9 and surprisingly, the pro enkephalin (Penk) gene. Subsequent bioinformatic analysis of available datasets indicated the molecular mechanisms that could explain specific Penk expression in Treg. Altogether, our results show that the meta-Treg signature concerns a very limited set of genes centered on the IL-2 family, members of the TNF receptor superfamily, and the endogenous opioid pathway.