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.
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).
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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- Immunology and Inflammation
Chronic antigenic stimulation can trigger the formation of interleukin 10 (IL-10)-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that murine T-follicular helper (TFH) cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is characterized by the progressive loss and acquisition of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Here, we use a broad range of bulk and single-cell transcriptional and epigenetic tools to investigate the epigenetic underpinnings of this process. At the single-cell level, the TFH-to-TR1 cell transition is accompanied by both, downregulation of TFH cell-specific gene expression due to loss of chromatin accessibility, and upregulation of TR1 cell-specific genes linked to chromatin regions that remain accessible throughout the transdifferentiation process, with minimal generation of new open chromatin regions. By interrogating the epigenetic status of accessible TR1 genes on purified TFH and conventional T-cells, we find that most of these genes, including Il10, are already poised for expression at the TFH cell stage. Whereas these genes are closed and hypermethylated in Tconv cells, they are accessible, hypomethylated, and enriched for H3K27ac-marked and hypomethylated active enhancers in TFH cells. These enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors TOX-2, IRF4, and c-MAF. Together, these data suggest that the TR1 gene expression program is genetically imprinted at the TFH cell stage.
