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 preprogrammed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL-6 was transiently expressed in iNKT cells upon exit from positive selection and was required for their proper development beyond stage 0. Notably, development of MAIT cells was also impaired in the absence of Bcl6. BCL-6-deficient iNKT cells had reduced expression of genes that were associated with the innate T cell lineage, including Zbtb16, which encodes PLZF, and PLZF-targeted genes. BCL-6 contributed to a chromatin accessibility landscape that was permissive for the expression of development-related genes and inhibitory for genes associated with naive T cell programs. Our results revealed new functions for BCL-6 and illuminated how this transcription factor controls early iNKT cell development.

先天T细胞，包括不变的自然杀伤T（iNKT）和与粘膜相关的先天T（MAIT）细胞，是异质性T淋巴细胞，其效应特性在胸腺分化过程中已预先编程。目前尚不清楚如何启动该程序。在这里，我们表明转录因子BCL-6在iNKT细胞中从阳性选择退出后瞬时表达，并且是其在0期以后正常发育所必需的。值得注意的是，在不存在Bcl6的情况下，MAIT细胞的发育也受到了损害。缺乏BCL-6的iNKT细胞具有与先天T细胞谱系相关的基因（包括Zbtb16）的表达降低，它编码PLZF和靶向PLZF的基因。BCL-6促进了染色质可及性的发展，它允许与发育相关的基因表达，并抑制与幼稚T细胞程序相关的基因。我们的结果揭示了BCL-6的新功能，并阐明了该转录因子如何控制早期iNKT细胞的发育。