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.
Reviewing Editor
- Satyajit Rath, Indian Institute of Science Education and Research (IISER), India
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).
Version history
- Received: October 8, 2019
- Accepted: February 10, 2020
- Accepted Manuscript published: February 10, 2020 (version 1)
- Version of Record published: February 17, 2020 (version 2)
- 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.
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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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- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
