The transcriptional repressor Bcl6 promotes pre-TCR-induced thymocyte differentiation and attenuates Notch1 activation.

Anisha Solanki,Tessa Crompton,Alessandro Barbarulo,Susan Ross,Jasmine Rowell,Hemant Sahni,Diana C Yánez,Ching-In Lau

doi:10.1242/dev.192203

Anisha Solanki, Tessa Crompton + Show 6 more

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https://doi.org/10.1242/dev.192203

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Abstract

Pre-T-cell receptor (TCR) signal transduction is required for developing thymocytes to differentiate from CD4-CD8- double-negative (DN) cell to CD4+CD8+ double-positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cells, disrupted expansion and enrichment of intracellular TCRβ+ cells within the DN population and increased DN4 cell death. Deletion also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-cell acute lymphoblastic leukaemia (T-ALL), and the involvement of BCL6 in other types of leukaemia, this study is important to our understanding of T-ALL.

Highlights

ΑβT cells develop in the thymus, which provides an essential environment for T-cell fate specification and differentiation (Koch and Radtke, 2011; Hosokawa and Rothenberg, 2018)
On E15.5, the Bcl6coKO thymus contained more thymocytes than the control, and there were no differences in the distribution of the DN subsets, the proportion of DN3 and DN4 cells that expressed intracellular TCRβ was higher in Bcl6coKO than in the control (Fig. 1A-D)
We show that Bcl6 is required for preTCR-induced differentiation from DN3 cell to DP cell and for attenuation of Notch1 activation

Summary

Introduction

ΑβT cells develop in the thymus, which provides an essential environment for T-cell fate specification and differentiation (Koch and Radtke, 2011; Hosokawa and Rothenberg, 2018). Notch activation promotes T-cell fate in bone marrow (BM)derived precursors entering the thymus, and mice deficient in Notch exhibit failed T-cell lineage commitment, whereas forced expression of Notch leads to generation of T cells in BM (Radtke et al, 2010; Hosokawa and Rothenberg, 2018). Notch signalling is maintained during β-selection (Ciofani and Zúñiga-Pflücker, 2005; Hosokawa and Rothenberg, 2018), but following pre-TCR signalling, Notch genes are downregulated as Id3 rises and supresses E2A-mediated transcription (Allman et al, 2001; Yashiro-Ohtani et al, 2009). Inappropriate Notch activation after β-selection is oncogenic and contributes to T-ALL (Tzoneva and Ferrando, 2012; Pelullo et al, 2014)

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