Fig. 1: The regulation of ILC2 functions by cytokines.

Activating cytokines such as IL-33 and IL-25 stimulate NF-κB translocation into the nucleus and activate the p38 MAPK pathway, resulting in GATA3 activation. Activation of NF-κB and GATA3 leads to the expression of genes involved in type 2 cytokine production, cell proliferation, survival, and metabolism. Costimulatory cytokines augment these effects in a synergistic manner. TSLP and members of the γc family of cytokines (IL-2, IL-7, IL-9, and IL-4) synergize with IL-33 through the JAK/STAT pathway, whereas TNF superfamily cytokines (TLA1 and TNF-α) act through the NF-κB pathway. Notably, IL-9 can act in an autocrine manner through IRF4. Inhibitory cytokines such as IFNs (both Type I and II) and IL-27 suppress ILC2 functions through the STAT1 pathway. The effects of TGF-β, on the other hand, are context dependent. While the mechanism underlying the suppressive effects of TGF-β is unclear, TGF-β stimulates ILC2s by promoting GATA3 expression through SOX4 inhibition (denoted in orange) or by activating the TGF-β coreceptor Nrp1 (blue dashed box). Moreover, TGF-β maintains Nrp1 expression through the canonical Smad pathway. Together with IL-1β and IL-23, TGF-β can act as a transdifferentiation cytokine that polarizes ILC2s into IL-17A-producing ILC3-like cells. Moreover, the combination of IL-1β, IL-18, and IL-12 converts ILC2s into IFN-γ-producing cells with ILC1-like properties. Notably, IL-4 inhibits ILC2 transdifferentiation. The full term for each abbreviation can be found in the text.