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

Authors
  • Tizian, Caroline1, 2
  • Lahmann, Annette3
  • Hölsken, Oliver1, 2
  • Cosovanu, Catalina1, 2
  • Kofoed-Branzk, Michael1, 2
  • Heinrich, Frederik4
  • Mashreghi, Mir-Farzin4
  • Kruglov, Andrey5, 6
  • Diefenbach, Andreas1, 2
  • Neumann, Christian1, 2
  • 1 Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany. , (Germany)
  • 2 Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany. , (Germany)
  • 3 Chronic Immune Reactions, Deutsches Rheuma-Forschungszentrum, Berlin, Germany. , (Germany)
  • 4 Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany. , (Germany)
  • 5 Chronic Inflammation, Deutsches Rheuma-Forschungszentrum, Berlin, Germany. , (Germany)
  • 6 Belozersky Institute of Physico-Chemical Biology and Biological Faculty, M.V. Lomonosov Moscow State University, Moscow, Russian Federation. , (Russia)
Type
Published Article
Journal
eLife
Publisher
"eLife Sciences Organisation, Ltd."
Publication Date
Feb 10, 2020
Volume
9
Identifiers
DOI: 10.7554/eLife.52549
PMID: 32039762
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

RORγt+ 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-1β, 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. © 2020, Tizian et al.

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