Transcriptome analysis of the Th17/Treg axis reveals multiple pathways that ensure distinct differentiation patterns

The Th17/ Treg axis is a crucial regulator of anti-inflammatory and proinflammatory pathways that play fundamental roles in cancer and autoimmune diseases. The alteration of the Th17/Tregs axis is highly significant for developing novel therapeutic approaches. Th17 and Treg cells share a large portion of their transcriptome, albeit with distinct functions. The mechanisms governing the bifurcation of Th17 /Treg axis differentiation from naive T cells are not yet understood. This study aims to identify the differentially expressed genes (DEGs) and gene-enriched pathways that contribute to the distinction between these closely aligned phenotypes. We analyzed RNA sequencing data of CD4+ T cells differentiated in vitro into Th0, Th17, and Tregs phenotypes and built gene enrichment networks. We studied the network rewiring of Th17 and Tregs from Th0 cells. In addition to common pathways and genes that are equally expressed between these two distinct phenotypes, we identified key genes and pathways that contribute to their distinctiveness. For example, the Keap1 gene and several of its interactors such as MCC1 were upregulated in Tregs indicating that Tregs possess mechanisms that prevent the over-activation of antioxidants pathways. Tregs also possess several genes that are involved in the hydrolysis of ATP to ADP as RAB37, ATP1A2, ATP1B, and PDE2A to ensure Treg anti-inflammatory capabilities. Additionally, one of the pathways that ensure Tregs differentiation and function seems to point toward an insulin role mediated by APOL9B and GOLM. Taken together our findings shed light on various essential regulators of the Th17/Treg axis and pave the way for treatment strategies that selectively target one phenotype while sparing the other.