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

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 low RO 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.

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

“…First, the bioactivity of IL-33 is limited in blood [33]. A study measured the serum levels of IL-33 in 30 healthy controls and found that all of the samples were undetectable (lowest limit of detection, 75 pg/mL) [33]. Future study addressing the role of IL-33 in AD can simultaneously measure IL-33 and its receptor ST2.…”

Enhanced CXCR4 Expression of Human CD8Low T Lymphocytes Is Driven by S1P4

“…Alongside T cell receptor (TCR) signaling and IL-2 stimulation, IL-12 is described as the “third signal” for the expansion of cytotoxic T c 1 immune cell responses. One focus of our recent report was to understand the role of IL-33 and IL-12 in CD8 + T lymphocyte differentiation under nutrient deprivation ( 28 ). The function of IL-33 is dependent not only on TCR signaling, but also on the presence of IL-12.…”

The Role of Interleukin-33 in Patients with Mild Cognitive Impairment and Alzheimer's Disease

“…Our study has limitations. First, the bioactivity of IL-33 is limited in blood [28]. A study measured the serum levels of IL-33 in 30 healthy controls and found that all of the samples were undetectable (lowest limit of detection: 75 pg/ml).…”