c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells

Abstract
Data availability
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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.

The following previously published data sets were used

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Article and author information

Author details

Caroline Tizian

Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Annette Lahmann

Chronic Immune Reactions, Deutsches Rheuma-Forschungszentrum, Berlin, Germany

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The authors declare that no competing interests exist.
Oliver Hölsken

Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6086-9275
Catalina Cosovanu

Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Michael Kofoed-Branzk

Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Frederik Heinrich

Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Mir-Farzin Mashreghi

Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8015-6907
Andrey Kruglov

Chronic Inflammation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Andreas Diefenbach

Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Christian Neuman

Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

For correspondence
c.neumann@charite.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2202-1876

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

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.