The transcription factor BCL-6 controls early development of innate-like T cells

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...

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Published inNature immunology Vol. 21; no. 9; pp. 1058 - 1069
Main Authors Gioulbasani, Marianthi, Galaras, Alexandros, Grammenoudi, Sofia, Moulos, Panagiotis, Dent, Alexander L, Sigvardsson, Mikael, Hatzis, Pantelis, Kee, Barbara L, Verykokakis, Mihalis
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.09.2020
Subjects
Animals
Bcl-6 protein
Cell Differentiation
Cell lineage
Cells, Cultured
Chromatin
Chromatin - metabolism
Clonal selection
Clonal Selection, Antigen-Mediated
Developmental stages
Gene expression
Gene Expression Regulation, Developmental
Genetic aspects
Health aspects
Immunity, Innate
Killer cells
Lymphocyte Activation
Lymphocytes
Lymphocytes T
Mice
Mice, Inbred C57BL
Mice, Knockout
Mucosa
Mucosal-Associated Invariant T Cells - immunology
Natural killer cells
Natural Killer T-Cells - immunology
Positive selection
Promyelocytic Leukemia Zinc Finger Protein - genetics
Proto-Oncogene Proteins c-bcl-6 - genetics
Proto-Oncogene Proteins c-bcl-6 - metabolism
T cells
Thymus
Transcription factors
Greece
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Summary: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.
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M.G. designed, performed and analyzed experiments. A.G. performed the bioinformatic analysis of the RNA-seq and ATAC-seq data and analyzed experiments under the supervision of P.M. and P.H. S.G. assisted with flow cytometry cell sorting and flow cytometry analysis. A.L.D. provided the Bcl6F/F mouse strain. M.S. performed the RNA-seq experiments. B.L.K. obtained funding, performed the ATAC-seq experiments, interpreted the data, reviewed and edited the manuscript. M.V. conceptualized the project, obtained funding, supervised research, interpreted the data, performed and analyzed experiments and wrote the manuscript. All authors have read and approved of the final manuscript.
Author Contributions
ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/s41590-020-0737-y