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
- Microbiology and Infectious Disease
The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28-/- mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.
