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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01698

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

Caroline Dreis1, Florian Ottenlinger1,  Mateusz Putyrski2, Andreas Ernst2, 3, Meik Huhn1,  Katrin G. Schmidt1, Josef M. Pfeilschifter1 and  Heinfried H. Radeke1*
  • 1Institute of Pharmacology and Toxicology, Goethe University Frankfurt am Main, Germany
  • 2Fraunhofer IME - Translational Medicine and Pharmacology (TMP), Germany
  • 3Institute of Clinical Pharmacology, University Hospital Frankfurt, Germany

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 mRNA expression of IFNg. 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.

Keywords: IL-33, Bioactivity, CD8+ T lymphocytes, ST2L, nutrient deprivation, mTOR

Received: 08 Apr 2019; Accepted: 08 Jul 2019.

Edited by:

Diana Boraschi, Istituto di biochimica delle proteine (IBP), Italy

Reviewed by:

Giuseppe Matarese, Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Italy
Giovanna Del Pozzo, Institute of Genetics and Biophysics (CNR), Italy  

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.

* Correspondence: Prof. Heinfried H. Radeke, Institute of Pharmacology and Toxicology, Goethe University Frankfurt am Main, Frankfurt am Main, Germany,