Tissue Cytokine IL-33 Modulates the Cytotoxic CD8 T Lymphocyte Activity During Nutrient Deprivation by Regulation of Lineage-Specific Differentiation Programs

Caroline Dreis; Florian M Ottenlinger; Mateusz Putyrski; Andreas Ernst; Meik Huhn; Katrin G Schmidt; Josef M Pfeilschifter; Heinfried H Radeke

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

Front Immunol. 2019 Jul 24:10:1698. doi: 10.3389/fimmu.2019.01698. eCollection 2019.

Authors

Caroline Dreis¹, Florian M Ottenlinger¹, Mateusz Putyrski², Andreas Ernst^{2

3}, Meik Huhn¹, Katrin G Schmidt¹, Josef M Pfeilschifter¹, Heinfried H Radeke¹

Affiliations

¹ pharmazentrum Frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, Frankfurt am Main, Germany.
² Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Frankfurt am Main, Germany.
³ Institute of Clinical Pharmacology, Goethe-University, Frankfurt am Main, Germany.

Abstract

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 CD45RA^lowRO^low 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.

Keywords: CD8+ T lymphocytes; IL-33; ST2L; bioactivity; mTOR; nutrient deprivation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / immunology*
HEK293 Cells
Humans
Interleukin-33 / immunology*
Lymphocyte Activation*
Male
T-Lymphocytes, Cytotoxic / cytology
T-Lymphocytes, Cytotoxic / immunology*

Substances

IL33 protein, human
Interleukin-33