WEI-BEI WANGMEN-LUH YENLiu K.-JHsu P.-JLin M.-HChen P.-MSudhir P.-RChen C.-HChen C.-HSytwu H.-KYen B.L.2020-02-112020-02-1120152213-6711https://scholars.lib.ntu.edu.tw/handle/123456789/457213Summary Multipotent human mesenchymal stromal cells (hMSCs) harbor immunomodulatory properties that are therapeutically relevant. One of the most clinically important populations of leukocytes is the interleukin-17A (IL-17A)-secreting T (Th17) lymphocytes. However, mechanisms of hMSC and Th17 cell interactions are incompletely resolved. We found that, along with Th1 responses, hMSCs strongly suppressed Th17 responses and this required both IL-25 - also known as IL-17E - as well as programmed death ligand-1 (PD-L1), a potent cell surface ligand for tolerance induction. Knockdown of IL-25 expression in hMSCs abrogated Th17 suppression in vitro and in vivo. However, IL-25 alone was insufficient to significantly suppress Th17 responses, which also required surface PD-L1 expression. Critically, IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. Our findings demonstrate the complexities of hMSC-mediated Th17 suppression, and highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target.In this article, Yen and colleagues demonstrate that multipotent human mesenchymal stromal cells (hMSCs) suppress interleukin (IL)-17A-secreting T cell (Th17) responses through expression of IL-25, a paracrine factor, and programmed death ligand-1 (PD-L1), a cell surface ligand. The requirement of both factors is explained by IL-25 modulation of PD-L1 expression via JNK and STAT3 to orchestrate an overall effect of suppressing Th17 responses. © 2015 The Authors.en[SDGs]SDG3journal article10.1016/j.stemcr.2015.07.0132-s2.0-84941184783