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

• Published in: eLife Vol. 12
• Main Authors: Thomas, Rajan M, Pahl, Matthew C, Wang, Liqing, Grant, Struan F A, Hancock, Wayne W, Wells, Andrew D
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 24.04.2024; eLife Sciences Publications, Ltd
• Subjects: Anergy; Animals; Antigens; Autoimmunity; Cell differentiation; Chromosomes and Gene Expression; Cytokines; DNA methylation; epigenetics; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene deletion; Gene expression; Gene Expression Regulation; Genomes; Ikaros protein; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - metabolism; Immunological tolerance; Immunology and Inflammation; Immunoregulation; Inflammation; Lymphatic system; Lymphocytes; Lymphocytes T; Mice; Mice, Knockout; Phosphorylation; Protein expression; Proteins; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; tolerance; transcription factors; Transcriptomes; Wnt protein; mouse; inflammation; transcription factors; chromosomes; immunology; epigenetics; gene expression; tolerance
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.91392

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 ( ). 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 production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While -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.