Abstract
Whereas effector CD4+ and CD8+ T cells promote immune activation and can drive clearance of infections and cancer, CD4+ regulatory T (Treg) cells suppress their function, contributing to both immune homeostasis and cancer immunosuppression. The transcription factor BACH2 functions as a pervasive regulator of T cell differentiation, promoting development of CD4+ Treg cells and suppressing the effector functions of multiple effector T cell (Teff) lineages. Here, we report the development of a stable cell-based bioluminescence assay of the transcription factor activity of BACH2. Tetracycline-inducible BACH2 expression resulted in suppression of phorbol 12-myristate 13-acetate (PMA)/ionomycin-driven activation of a luciferase reporter containing BACH2/AP-1 target sequences from the mouse Ifng + 18k enhancer. BACH2 expression repressed the luciferase signal in a dose-dependent manner but this activity was abolished at high levels of AP-1 signalling, suggesting contextual regulation of AP-1 driven gene expression by BACH2. Finally, using the reporter assay developed, we find that the histone deacetylase 3 (HDAC3)-selective inhibitor, RGFP966, inhibits BACH2-mediated repression of signal-driven luciferase expression. In addition to enabling mechanistic studies, this cell-based reporter may enable identification of small molecule agonists or antagonists of BACH2 function for drug development.
Highlights
Whereas effector CD4+ and CD8+ T cells promote immune activation and can drive clearance of infections and cancer, CD4+ regulatory T (Treg) cells suppress their function, contributing to both immune homeostasis and cancer immunosuppression
Important among extrinsic immunoregulatory mechanisms is the activity of CD4+ regulatory T (Treg) cells which limit Tconv cell function and promote immune homeostasis and tumour immunosuppression[1,2,3,4,5,6]
We observed a loss of BACH2-mediated luciferase signal repression at higher levels of phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation (Fig. 5a, b). These results suggest that BACH2 capacity to mediate activator protein 1 (AP-1)-driven gene expression repression is reduced in the presence of strong activating signals
Summary
Whereas effector CD4+ and CD8+ T cells promote immune activation and can drive clearance of infections and cancer, CD4+ regulatory T (Treg) cells suppress their function, contributing to both immune homeostasis and cancer immunosuppression. CD8+ and CD4+ conventional T (Tconv) cells drive immune activation and promote clearance of infections and cancer Their function can provoke autoimmune and allergic inflammation. Important among extrinsic immunoregulatory mechanisms is the activity of CD4+ regulatory T (Treg) cells which limit Tconv cell function and promote immune homeostasis and tumour immunosuppression[1,2,3,4,5,6]. Appropriate control of T cell differentiation and function requires that they are able to rapidly regulate their gene‐expression programs in response to extrinsic signals Such capacity is provided by transcription factors (TFs), which bind to the available repertoire of regulatory DNA elements in distinct lymphocyte subsets to program cell‐type‐specific gene e xpression[7]. The BACH2 gene in humans is a prominent risk locus for multiple autoimmune and allergic d iseases[12]
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