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.