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 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.
Highlights
Interleukin (IL)-1 family member IL-33 (IL-1F11) was recently identified as the missing ligand for ST2L (IL-1RL1, IL-1R4) and was primarily associated to immune cells with a T helper 2 (Th2) phenotype [1]
Bioactivity was detected by indirect measurement of IL-33 induced NF-κB activity, which subsequently initiates expression of secreted alkaline phosphatase (SEAP) and conversion of an exogenously added substrate
We suggested that soluble decoy receptor ST2 (sST2) represents a major regulator of IL-33 bioactivity in blood, IL-33 bioactivity might primarily be inhibited by intra-molecular mechanisms promptly upon release from cellular sources
Summary
Interleukin (IL)-1 family member IL-33 (IL-1F11) was recently identified as the missing ligand for ST2L (IL-1RL1, IL-1R4) and was primarily associated to immune cells with a T helper 2 (Th2) phenotype [1]. IL-33 exerts a dual function as an intranuclear negative regulator of NF-κB and extracellularly as a cytokine potently co-stimulating adaptive immune responses far beyond Th2 immunity, offering new targets for the activation of anti-tumoral cytotoxic T cells [2,3,4]. Impairment of nutrient delivery resulting from an abnormally structured vascular system in tumor tissue induces diverse cellular stress responses and influences the fitness of tumor infiltrating T cells [17, 18]. MTOR is activated under nutrient rich conditions, inhibited during nutrient deficiencies and has a central role in the regulation of autophagy, T cell differentiation and memory generation [19, 20]. Our study focused on the regulation of IL-33 bioactivity by soluble decoy receptor ST2 (sST2), by intra-molecular modifications and on the cellular level by differentially modulating IL-33 responsivity under nutrient deprivation. We show for the first time, that nutrient deprivation
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