1. Immunology and Inflammation
Download icon

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

  1. Caroline Tizian
  2. Annette Lahmann
  3. Oliver Hölsken
  4. Catalina Cosovanu
  5. Michael Kofoed-Branzk
  6. Frederik Heinrich
  7. Mir-Farzin Mashreghi
  8. Andrey Kruglov
  9. Andreas Diefenbach
  10. Christian Neuman  Is a corresponding author
  1. Charité-Universitätsmedizin Berlin, Germany
  2. Deutsches Rheuma-Forschungszentrum, Germany
Short Report
  • Cited 1
  • Views 992
  • Annotations
Cite this article as: eLife 2020;9:e52549 doi: 10.7554/eLife.52549

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.

Article and author information

Author details

  1. Caroline Tizian

    Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Annette Lahmann

    Chronic Immune Reactions, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Oliver Hölsken

    Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6086-9275
  4. Catalina Cosovanu

    Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. 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.
  6. Frederik Heinrich

    Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Mir-Farzin Mashreghi

    Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8015-6907
  8. Andrey Kruglov

    Chronic Inflammation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Andreas Diefenbach

    Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. 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.
    ORCID icon "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).

Reviewing Editor

  1. Satyajit Rath, Indian Institute of Science Education and Research (IISER), India

Publication history

  1. Received: October 8, 2019
  2. Accepted: February 10, 2020
  3. Accepted Manuscript published: February 10, 2020 (version 1)
  4. Version of Record published: February 17, 2020 (version 2)
  5. 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.

Metrics

  • 992
    Page views
  • 176
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation
    Chew Leng Lim et al.
    Research Article Updated

    There is strong evidence that the pro-inflammatory microenvironment during post-partum mammary involution promotes parity-associated breast cancer. Estrogen exposure during mammary involution drives tumor growth through neutrophils’ activity. However, how estrogen and neutrophils influence mammary involution are unknown. Combined analysis of transcriptomic, protein, and immunohistochemical data in BALB/c mice showed that estrogen promotes involution by exacerbating inflammation, cell death and adipocytes repopulation. Remarkably, 88% of estrogen-regulated genes in mammary tissue were mediated through neutrophils, which were recruited through estrogen-induced CXCR2 signalling in an autocrine fashion. While neutrophils mediate estrogen-induced inflammation and adipocytes repopulation, estrogen-induced mammary cell death was via lysosome-mediated programmed cell death through upregulation of cathepsin B, Tnf and Bid in a neutrophil-independent manner. Notably, these multifaceted effects of estrogen are mostly mediated by ERα and unique to the phase of mammary involution. These findings are important for the development of intervention strategies for parity-associated breast cancer.