DNA methylation profiling of human CD4+ T helper cells reveals the epigenetic control of SLAMF7 expression in IFN-γ producing cells

Naive CD4+ T cells are highly plastic cells that can differentiate into various T helper (Th) cell subsets upon activation. It is well accepted that the vital expression of specific transcription factors and effector cytokines that characterize the different Th cell fates can be stabilized by epigenetic mechanisms including DNA methylation. However, a global view on DNA methylation profiles in Th cell subsets is currently lacking. In this study, we identified the DNA methylomes of human naive T cells, Th1, nonclassic Th1, and Th17 cells by performing a whole-genome bisulfite sequencing analysis. Differentially methylated regions (DMRs) obtained by pairwise comparison of the Th cell methylomes indicate a close relationship between ncTh1 and Th17 cells on a genome-wide level. However, similar methylation patterns at key gene loci such as TBX21, IFNG, SLAMF7, and SLAMF8 may explain the functional proximity of ncTh1 to Th1 cells. Using luciferase reporter assays, we demonstrated that DNA methylation can modulate the transcriptional activity of promoter-located DMRs belonging to genes such as GSPT1, SRSF7, SLAMF7, SLAMF8, TIGIT, and PDCD1. Upon stimulation, SLAMF7 gene expression was upregulated exclusively in IFN-γ producing cells, with SLAMF7+ cells appearing among both Th1 and ncTh1 cells. Taken together, the DNA methylomes of proinflammatory human Th cells provide useful data for better functional characterization of the lineages and identification of key genes for therapeutic intervention.