IL-31 and the immune system
The source of IL-31 and the factors modulating IL-31 expression are still poorly understood. Several studies point to a preferential expression of IL-31 in mice and humans by CD3+CD4+ type 2 T-helper cells (TH2).1,5,9,10 A recent large-scale tissue bank screening approach confirmed almost exclusive expression of IL-31 by CD3+ CD4+ immune cells.11 Stott et al . propose that in humans IL-31 expression in CD3+ CD4+TH2 cells is under primary control of IL-4 whereas IL-33 stimulation seems to boost IL-31 secretion human TH2 cells via a STAT6-dependent regulation of T1/ST2 receptor.9,11,12 In contrast, TGF-β has a rather damping effect on IL-31 secretion via phosphorylation of SMAD2/3 molecules. This effect might explain why fully differentiated TH9 cells express only moderate IL-31 levels since differentiation of TH9 is initiated by co-stimulation with IL-4 and TGF-β. While the IL-4 signal initiates IL-31 expression, the simultaneous TGF-β signal dampens IL-31 expression counter-regulating the IL-4 effect. TH2 cells, in comparison, are not relying on TGF-β as they differentiate from naïve T cells dependent on IL-4 signaling from the microenvironment alone and maintain their phenotype by autocrine IL-4 signaling which in parallel supports IL-31 expression.9 The transcription of theIl31 gene in TH2 and (probably IL-4 producing) mast cells is under control of calcium-dependent NFAT1 and NFAT2 and a ‘usual suspect’ of cytokine expression regulators, the protein family of suppressor of cytokine signaling (SOCS), was found to have a pivotal role in suppression of ‘uncontrolled’ IL-31 expression (Figure 1).13,14 However, it remains unclear how secretion of IL-31 is restricted to IL-4-expressing cells (TH2 cells in particular) and if IL-31+ TH2 cells could mark a distinct subpopulation within TH2 cells. Notably, our knowledge about the communication between IL-31 and IL-13 or TSLP is very poor.