Identification of the novel FOXP3-dependent T(reg) cell transcription factor MEOX1 by high-dimensional analysis of human CD4(+) T cells

CD4(+) T cells play a central role in the adaptive immune response through their capacity to activate, support and control other immune cells. Although these cells have become the focus of intense research, a comprehensive understanding of the underlying regulatory networks that orchestrate CD4(+) T cell function and activation is still incomplete. Here, we analyzed a large transcriptomic dataset consisting of 48 different human CD4(+) T cell conditions. By performing reverse network engineering, we identified six common denominators of CD4(+) T cell functionality (CREB1, E2F3, AHR, STAT1, NFAT5 and NFATC3). Moreover, we also analyzed condition-specific genes which led us to the identification of the transcription factor MEOX1 in T(reg) cells. Expression of MEOX1 was comparable to FOXP3 in T(reg) cells and can be upregulated by IL-2. Epigenetic analyses revealed a permissive epigenetic landscape for MEOX1 solely in T(reg) cells. Knockdown of MEOX1 in T(reg) cells revealed a profound impact on downstream gene expression programs and T(reg) cell suppressive capacity. These findings in the context of CD4(+) T cells contribute to a better understanding of the transcriptional networks and biological mechanisms controlling CD4(+) T cell functionality, which opens new avenues for future therapeutic strategies.