RESUMEN
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.
Asunto(s)
Cromatina/metabolismo , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Asesinas Naturales/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Animales , Diferenciación Celular , Células Cultivadas , Selección Clonal Mediada por Antígenos , Regulación del Desarrollo de la Expresión Génica , Inmunidad Innata , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína de la Leucemia Promielocítica con Dedos de Zinc/genética , Proteínas Proto-Oncogénicas c-bcl-6/genéticaRESUMEN
The WNT/ß-catenin signaling pathway controls a plethora of biological processes throughout animal development and adult life. Because of its fundamental role during animal lifespan, the WNT pathway is subject to strict positive and negative multi-layered regulation, while its aberrant activity causes a wide range of pathologies, including cancer. At present, despite the inroads into the molecules involved in WNT-mediated transcriptional responses, the fine-tuning of WNT pathway activity and the totality of its target genes have not been fully elucidated. Over the past few years, long non-coding RNAs (lncRNAs), RNA transcripts longer that 200nt that do not code for proteins, have emerged as significant transcriptional regulators. Recent studies show that lncRNAs can modulate WNT pathway outcome by affecting gene expression through diversified mechanisms, from the transcriptional to post-translational level. In this review, we selectively discuss those lncRNA-mediated mechanisms we believe the most important to WNT pathway modulation.