IL17 factors are early regulators in the gut epithelium during inflammatory response to Vibrio in the sea urchin larva
- The George Washington University, United States
- Sunnybrook Research Institute, Canada
- Saitama University, Japan
- University of Toronto, Canada
Abstract
IL17 cytokines are central mediators of mammalian immunity. In vertebrates, these factors derive from diverse cellular sources. Sea urchins share a molecular heritage with chordates that includes the IL17 system. Here, we characterize the role of epithelial expression of IL17 in the larval gut-associated immune response. The purple sea urchin genome encodes ten IL17 subfamilies (35 genes) and two IL17 receptors. Most of these subfamilies are conserved throughout echinoderms. Two IL17 subfamilies are sequentially strongly upregulated and attenuated in the gut epithelium in response to bacterial disturbance. IL17R1 signal perturbation results in reduced expression of several response genes including an IL17 subtype, indicating a potential feedback. A third IL17 subfamily is activated in adult immune cells indicating that expression in immune cells and epithelia is divided among families. The larva provides a tractable model to investigate the regulation and consequences of gut epithelial IL17 expression across the organism.
Data availability
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Strongylocentrotus purpuratus developmental transcriptomesPublicly available at the NCBI Gene Expression Omnibus (accession no: PRJNA81157).
Article and author information
Author details
Katherine M Buckley
Jonathan Patrick Rast
Funding
Canadian Institutes of Health Research (MOP74667)
- Jonathan Patrick Rast
Natural Sciences and Engineering Research Council of Canada (312221)
- Jonathan Patrick Rast
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Sarah Gaffen
Ethics
Animal experimentation: All animal care and use protocols were approved by the Sunnybrook Research Institute Animal Care Committee
Version history
- Received: November 19, 2016
- Accepted: April 25, 2017
- Accepted Manuscript published: April 27, 2017 (version 1)
- Version of Record published: June 2, 2017 (version 2)
Copyright
© 2017, Buckley 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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IL17 factors are early regulators in the gut epithelium during inflammatory response to Vibrio in the sea urchin larva
eLife 6:e23481.
https://doi.org/10.7554/eLife.23481
Further reading
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The sea urchin may be a good model for understanding how immune responses work in humans and other vertebrates.
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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.
