IL-9 is a pleiotropic cytokine, for which an overarching role in humans remains elusive. Recent research shows that Interleukin 9 (IL-9) and its receptor, IL-9R, are predominantly expressed by skin-tropic T helper 2 (TH2) cells. This hence suggests that autocrine or paracrine IL-9 signals play an important role in cutaneous immunity and allergy. Yet, the mechanism of action remains incompletely understood. Here, we aimed at deciphering the effect of IL-9 on TH cells in allergic skin inflammation. To this end, we isolated human TH cells from acute atopic contact dermatitis biopsies, expressing high levels of IL-9R. Transcriptional profiling showed that approx. 800 genes are differentially expressed in response to IL-9. Pathway analysis revealed that upregulated genes are associated with conventional TH2 immune response. Strikingly, we observed a strong induction of genes specifically associated with the pathogenic TH2 phenotype, such as IL9, IL17RB and HPGDS. In addition, we found that IL-9-stimulated TH cells showed a coordinated induction of genes involved in aerobic glycolysis. On protein level, we confirmed that IL-9 prominently induced the expression of the monocarboxylate transporter 1 (MCT1), which is key for the export of lactate, the end product of aerobic glycolysis. As a functional consequence, IL-9 boosted glycolytic capacity and cell proliferation, which was abrogated by inhibition MCT1. Together, our data delineates that IL-9 not only promotes pathogenic features, but also provides a proliferative advantage to skin-tropic TH cells. These unrecognized roles of IL-9 might open up novel strategies for targeted manipulation of TH cells in allergic skin inflammation.

IL-9 is a pleiotropic cytokine, for which an overarching role in humans remains elusive. Recent research shows that Interleukin 9 (IL-9) and its receptor, IL-9R, are predominantly expressed by skin-tropic T helper 2 (T~H~2) cells. This hence suggests that autocrine or paracrine IL-9 signals play an important role in cutaneous immunity and allergy. Yet, the mechanism of action remains incompletely understood. Here, we aimed at deciphering the effect of IL-9 on T~H~ cells in allergic skin inflammation. To this end, we isolated human T~H~ cells from acute atopic contact dermatitis biopsies, expressing high levels of IL-9R. Transcriptional profiling showed that approx. 800 genes are differentially expressed in response to IL-9. Pathway analysis revealed that upregulated genes are associated with conventional T~H~2 immune response. Strikingly, we observed a strong induction of genes specifically associated with the pathogenic T~H~2 phenotype, such as _IL9_, _IL17RB_ and _HPGDS_. In addition, we found that IL-9-stimulated T~H~ cells showed a coordinated induction of genes involved in aerobic glycolysis. On protein level, we confirmed that IL-9 prominently induced the expression of the monocarboxylate transporter 1 (MCT1), which is key for the export of lactate, the end product of aerobic glycolysis. As a functional consequence, IL-9 boosted glycolytic capacity and cell proliferation, which was abrogated by inhibition MCT1. Together, our data delineates that IL-9 not only promotes pathogenic features, but also provides a proliferative advantage to skin-tropic T~H~ cells. These unrecognized roles of IL-9 might open up novel strategies for targeted manipulation of T~H~ cells in allergic skin inflammation.

ESDR005 - IL-9 promotes a pathogenic phenotype and enhances proliferation in skin-tropic TH cells

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.