c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells
- Charité-Universitätsmedizin Berlin, Germany
- Deutsches Rheuma-Forschungszentrum, Germany
Abstract
RORgt+ group 3 innate lymphoid cells (ILC3s) maintain intestinal homeostasis through secretion of type 3 cytokines such as interleukin (IL)-17 and IL-22. However, CCR6- ILC3s additionally co-express T-bet allowing for the acquisition of type 1 effector functions. While T-bet controls the type 1 programming of ILC3s, the molecular mechanisms governing T-bet are undefined. Here, we identify c-Maf as a crucial negative regulator of murine T-bet+ CCR6- ILC3s. Phenotypic and transcriptomic profiling of c-Maf-deficient CCR6- ILC3s revealed a hyper type 1 differentiation status, characterized by overexpression of ILC1/NK cell-related genes and downregulation of type 3 signature genes. On the molecular level, c-Maf directly restrained T-bet expression. Conversely, c-Maf expression was dependent on T-bet and regulated by IL-1b, IL-18 and Notch signals. Thus, we define c-Maf as a crucial cell-intrinsic brake in the type 1 effector acquisition which forms a negative feedback loop with T-bet to preserve the identity of CCR6- ILC3s.
Data availability
Sequencing data supporting the findings of this study have been deposited in the Gene Expression Omnibus (GEO) database under the GEO accession number: RNA-Seq: GSE143867.
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ChIP-seq analysis of T-bet in WT mice (Th1 cells)NCBI Gene Expression Omnibus, GSE40623.
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Integrated analysis of epigenome and transcriptome data from innate lymphoid cells and their progenitorsNCBI Gene Expression Omnibus, GSE77695.
Article and author information
Author details
Mir-Farzin Mashreghi
Funding
Deutsche Forschungsgemeinschaft (Priority Program 1937 "Innate Lymphoid Cells")
- Christian Neuman
Deutsche Forschungsgemeinschaft (Priority Program 1937 "Innate Lymphoid Cells")
- Andreas Diefenbach
European Regional Development Fund (ERDF 2014-2020)
- Mir-Farzin Mashreghi
European Regional Development Fund (EFRE 1.8/11)
- Mir-Farzin Mashreghi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Satyajit Rath, Indian Institute of Science Education and Research (IISER), India
Ethics
Animal experimentation: All animal experiments were in accordance with the ethical standards of the institution or practice at which the studies were conducted and were reviewed and approved by the responsible ethics committees (LAGeSo Berlin, I C 113 - G0172/14).
Version history
- Received: October 8, 2019
- Accepted: February 10, 2020
- Accepted Manuscript published: February 10, 2020 (version 1)
- Version of Record published: February 17, 2020 (version 2)
- Version of Record updated: March 10, 2020 (version 3)
Copyright
© 2020, Tizian et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells
eLife 9:e52549.
https://doi.org/10.7554/eLife.52549
Further reading
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