The transcription factor BCL6 controls early development of innate-like T cells (RNA-seq)

Innate T cells, including invariant natural killer T (iNKT) and mucosal-associated innate T (MAIT) cells, are a heterogeneous T lymphocyte population with effector properties pre-programmed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL6 is transiently expressed in iNKT cells upon exit from positive selection and is required for their proper development beyond stage 0. Notably, development of MAIT cells is also impaired in Bcl6-deficient mice. We found that BCL6 regulates the expression of genes that are associated with the innate T cell lineage, including PLZF and its targets. BCL6 contributes to a chromatin accessibility landscape that is permissive for the expression of development-related genes and inhibitory for genes associated with naïve T cell programs. Our results reveal novel functions for BCL6 and indicate that this transcription factor controls the inception of innate T cell lineage programming. Overall design: Tetramer+TCRb+CD24+CD44- (Stage 0, ST0) and Tetr+TCRb+CD24-CD44- (ST1) cells from the thymi of 4-7 pooled WT and CDCre;Bcl6F/F (Bcl6KO) mice were sorted and RNA was extracted for RNA-seq analysis. Similar populations were sorted and cells were porcessed for ATAC-seq.