Tissue cytokine IL-33 modulates the cytotoxic CD8 t lymphocyte activity during nutrient deprivation by regulation of lineage-specific differentiation programs

  • IL-1 family member IL-33 exerts a variety of immune activating and regulating properties and has recently been proposed as a prognostic biomarker for cancer diseases, although its precise role in tumor immunity is unclear. Here we analyzed in vitro conditions influencing the function of IL-33 as an alarmin and a co-factor for the activity of cytotoxic CD8+ T cells in order to explain the widely discussed promiscuous behavior of IL-33 in vivo. Circulating IL-33 detected in the serum of healthy human volunteers was biologically inactive. Additionally, bioactivity of exogenous recombinant IL-33 was significantly reduced in plasma, suggesting local effects of IL-33, and inactivation in blood. Limited availability of nutrients in tissue causes necrosis and thus favors release of IL-33, which—as described before—leads to a locally high expression of the cytokine. The harsh conditions however influence T cell fitness and their responsiveness to stimuli. Nutrient deprivation and pharmacological inhibition of mTOR mediated a distinctive phenotype characterized by expression of IL-33 receptor ST2L on isolated CD8+ T cells, downregulation of CD8, a transitional CD45RAlowROlow phenotype and high expression of secondary lymphoid organ chemokine receptor CCR7. Under nutrient deprivation, IL-33 inhibited an IL-12 induced increase in granzyme B protein expression and increased expression of GATA3 and FOXP3 mRNA. IL-33 enhanced the TCR-dependent activation of CD8+ T cells and co-stimulated the IL-12/TCR-dependent expression of IFNγ. Respectively, GATA3 and FOXP3 mRNA were not regulated during TCR-dependent activation. TCR-dependent stimulation of PBMC, but not LPS, initiated mRNA expression of soluble IL-33 decoy receptor sST2, a control mechanism limiting IL-33 bioactivity to avoid uncontrolled inflammation. Our findings contribute to the understanding of the compartment-specific activity of IL-33. Furthermore, we newly describe conditions, which promote an IL-33-dependent induction of pro- or anti-inflammatory activity in CD8+ T cells during nutrient deprivation.

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Author:Caroline Dreis, Florian Ottenlinger, Mateusz Putyrski, Andreas Ernst, Meik Huhn, Katrin G. Schmidt, Josef Martin PfeilschifterGND, Heinfried Hermann RadekeORCiDGND
URN:urn:nbn:de:hebis:30:3-507667
DOI:https://doi.org/10.3389/fimmu.2019.01698
ISSN:1664-3224
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31396219
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Diana Boraschi
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/07/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/08/22
Tag:CD8+ T lymphocytes; IL-33; ST2L; bioactivity; mTOR; nutrient deprivation
Volume:10
Issue:Art. 1698
Page Number:15
First Page:1
Last Page:15
Note:
Copyright © 2019 Dreis, Ottenlinger, Putyrski, Ernst, Huhn, Schmidt, Pfeilschifter and Radeke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
HeBIS-PPN:453728111
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0