102 IL-9 induces a type I interferon signature in pathogenic skin-tropic TH2 cells

IL-9 is a pleiotropic cytokine, for which an overarching role in humans remains elusive. Both interleukin 9 (IL-9) and its receptor, IL-9R, are specifically expressed by skin-tropic T helper 2 (TH2) cells. This suggests that IL-9 signals play an important role in cutaneous immunity and allergy. Yet, the mechanism of action of IL-9 remains incompletely understood. In this study, we aimed at deciphering the effect of IL-9 signals on TH cells in allergic skin inflammation. We isolated human IL-9R+ TH2 cells from blood and skin of allergic contact dermatitis and performed transcriptional profiling in presence of IL-9. Our results show that IL-9 regulated expression of approx. 800 genes. Upregulated genes were associated with TH2 immune response and, surprisingly, revealed a strong induction of interferon-stimulated genes (ISGs) such as IFIT3, RSAD2, and OAS1. Moreover, IL-9 enhanced the expression of i) IRF9 and STAT1, which together with STAT2 form the ISGF3 complex, and ii) the two subunits of the DTX3L-PARP9 dimer. Both, ISGF3 and DTX3L-PARP9, are well-known transcription factor complexes that amplify type-1 interferon responses. Hence, our data suggests that IL-9 induces a type I interferon signature in IL-9R+ TH2 cells and sensitizes them to type I interferon signals. Since ISG expression is usually mediated through STAT1 phosphorylation, we next investigated IL-9R signaling in detail. Interestingly, we found that signal transduction by IL-9R indeed leads to a strong phosphorylation of STAT3, STAT5 as well as STAT1. Thus, STAT1 phosphorylation by IL-9 results in a unique signaling profile that is not comparable to other members of the common gamma-chain-cytokine receptor family. In summary, we found that IL-9 signals induce a type I interferon signature in IL-9R+ TH2 cells through a unique STAT1 signaling profile. Therefore, our data suggests that IL-9 may enhance interferon-dependent immunity in type-2 inflammation and may thereby play an important role in providing protection against viral infections.