Selective disruption of RORγt-CBFβ interaction by IMU-935 prevents RORγt-dependent Th17 autoimmunity but not thymocyte development
Hongmin Wu, Xiancai Zhong, Ning Ma, Zhiheng He, Guanpeng Wang, Geming Lu, Yate-Ching Yuan, Wencan Zhang, Yun Shi, Nagarajan Vaidehi, Evelyn Peelen, Tanja Wulff, Christian Gege, Hella Kohlhof, Daniel Vitt, Yousang Gwack, Ichiro Taniuchi, Hai-Hui Xue, Zuoming Sun
Hongmin Wu, Xiancai Zhong, Ning Ma, Zhiheng He, Guanpeng Wang, Geming Lu, Yate-Ching Yuan, Wencan Zhang, Yun Shi, Nagarajan Vaidehi, Evelyn Peelen, Tanja Wulff, Christian Gege, Hella Kohlhof, Daniel Vitt, Yousang Gwack, Ichiro Taniuchi, Hai-Hui Xue, Zuoming Sun
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Research Article Autoimmunity Immunology

Selective disruption of RORγt-CBFβ interaction by IMU-935 prevents RORγt-dependent Th17 autoimmunity but not thymocyte development

Abstract

RORγt is a key transcription factor regulating both Th17 differentiation and thymocyte development. Although Th17 cells drive autoimmune diseases, inhibiting RORγt to treat autoimmunity also disrupts thymocyte development and can cause lethal thymic lymphoma. We identified a previously unreported RORγt cofactor, CBFβ, and a highly selective RORγt inhibitor, IMU-935, that preferentially disrupt the RORγt-CBFβ interaction in Th17 cells but not thymocytes. This interaction is essential for RORγt function; mice with a RORγt mutant unable to bind CBFβ had impaired Th17 differentiation, were resistant to experimental autoimmune encephalomyelitis (EAE), and had defective thymocyte development. IMU-935 inhibited Th17 differentiation and reduced EAE severity without affecting thymocyte development by selectively targeting the RORγt-CBFβ interaction in Th17 cells but not in thymocytes. This differential effect arose because different concentrations of IMU-935 were required to disrupt the interaction in Th17 cells versus thymocytes, due to varying levels of RUNX1 that compete with RORγt for CBFβ binding. This study reveals an unreported mechanism for RORγt regulation and a selective RORγt inhibitor that prevents Th17-driven autoimmunity without the risk of lethal lymphoma from thymocyte disruption.

Authors

Hongmin Wu, Xiancai Zhong, Ning Ma, Zhiheng He, Guanpeng Wang, Geming Lu, Yate-Ching Yuan, Wencan Zhang, Yun Shi, Nagarajan Vaidehi, Evelyn Peelen, Tanja Wulff, Christian Gege, Hella Kohlhof, Daniel Vitt, Yousang Gwack, Ichiro Taniuchi, Hai-Hui Xue, Zuoming Sun

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Figure 2

IMU-935 prevents Th17-dependent EAE via inhibiting Th17 differentiation.

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IMU-935 prevents Th17-dependent EAE via inhibiting Th17 differentiation....
(A) Flow cytometric analysis of IL-17A+ or IL-17F+ cells among RORγt–/– CD4+ T cells transduced with retrovirus expressing GFP alone (EV) or with WT RORγt and polarized under Th17 conditions for 60 hours with or without IMU-935. Numbers are the percentages of cells in gated areas throughout, IL-17A+ (n = 4/group, from 4 experiments) and IL-17F+ (n = 3/group, from 3 experiments) CD4+ T cells. (B) qRT-PCR analysis of indicated Th17 signature gene expression among differentiated Th17 cells without (–; pink) or with (+; red) 500 nM IMU-935 shown in A (n = 3/group, from 3 experiments). (C) Clinical score of EAE among EAE-induced mice (n = 6/group) and treated with vehicle or indicated concentrations of IMU-935 daily for the duration of the experiment. (D) Absolute number of indicated lymphocytes recovered from the CNS of the mice described in C. (E) Numbers of CD4+ T cells producing indicated cytokines in the CNS of the mice described in C. Data were assessed by 1-way ANOVA with Dunnett’s post hoc test (A, B, D and E) or 2-tailed Student’s t test (C). *P < 0.05; **P < 0.01.