Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function

• DOI: 10.7554/elife.91392.2
• Publication Date: 2024-03-26T13:25:19Z
• Authors: Rajan M. Thomas; Matthew C. Pahl; Liqing Wang; Struan F. A. Grant; Wayne W. Hancock; Andrew D. Wells
• Keywords: Mice, Knockout; tolerance; epigenetics; QH301-705.5; Science; Q; R; Forkhead Transcription Factors; Chromosomes and Gene Expression; T-Lymphocytes, Regulatory; Ikaros Transcription Factor; Mice; Gene Expression Regulation; transcription factors; Medicine; Animals; Biology (General)

Abstract Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal expression of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.