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 Dining Chairs 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 ALL PURPOSE CL IL-33-dependent induction of pro- or anti-inflammatory activity in CD8+ T cells during nutrient deprivation.