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

Thomas, R. M.; Pahl, M. C.; Wang, L.; Grant, S. F.; Hancock, W. W.; WELLS, A. D.

doi:10.1101/2023.05.23.541951

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bioRxiv · 10.1101/2023.05.23.541951

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

Thomas, R. M.·Pahl, M. C.·Wang, L.·Grant, S. F.·Hancock, W. W.·WELLS, A. D.

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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.

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Thomas, R. M., Pahl, M. C., Wang, L., Grant, S. F., Hancock, W. W., WELLS, A. D.. 2023-05-24. Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function. https://doi.org/10.1101/2023.05.23.541951

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