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

Abstract

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.

Keywords: Foxp3; MEOX1; Treg cells; human CD4; regulatory T cells.