Immunology Letters 160 (2014) 79–88 Contents lists available at ScienceDirect Immunology Letters j ourna l ho me page: www.elsevier.com/locate/immlet PIAS3 suppresses acute graft-versus-host disease by modulating effector T and B cell subsets through inhibition of STAT3 activation Sung-Hee Lee a,b , Su-Jin Moon c , Min-Jung Park a,b , Eun-Kyung Kim a,b , Young-Mee Moon a,b , Mi-La Cho a,b,∗ a The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea b Laboratory of Immune Network, Conversant Research Consortium in Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, South Korea c Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea a r t i c l e i n f o Article history: Received 20 January 2014 Received in revised form 28 March 2014 Accepted 28 March 2014 Available online 6 April 2014 Keywords: PIAS3 Graft-versus-host-disease STAT3 T cells B cells a b s t r a c t Graft-versus-host disease (GVHD) caused by transplanted donor T cells remains the major obstacle of allo- geneic bone marrow transplantation (BMT). Previous reports have suggested that IL-17-producing helper T (Th17) cells mediate the development of acute GVHD (aGVHD). Protein inhibitor of activated STAT3 (PIAS) inhibits the activity of the transcription factor STAT3, which is a pivotal transcription factor for Th17 differentiation. To elucidate whether PIAS3 could inhibit the development of aGVHD, pcDNA-PIAS3 or mock vector was administered in a murine model of aGVHD by intramuscular injection and subsequent electroporation. The results demonstrated that PIAS3 overexpression by pcDNA-vector administration significantly attenuated the clinical severity and histopathological severities of aGHVD involving the skin, liver, intestine, and lung. Additionally, the STAT3 activities in aGVHD target organs were suppressed by PIAS3 overexpression. Furthermore, phosphorylated (p) STAT3 activity in the spleen was profoundly attenuated in PIAS3-overexpressing GVHD mice. Interestingly, flow cytometric analysis demonstrated that the populations of CD21 high CD23 low marginal zone B cells were dramatically expanded in PIAS3- overexpressing mice. PIAS3-induced inhibition of aGVHD was largely related to the downregulation of Th1 and Th17 and the upregulation of Th2 and Treg populations. Both populations of pSTAT3 Tyr705 - expressing Th17 cells and B cells were significantly reduced in the spleens of PIAS3-overexpressing mice, whereas pSTAT5 activity was increased. In addition to CD4 + CD25 + Foxp3 + Treg cells, the populations of CD8 + CD25 + Foxp3 + Treg cells were also expanded by treatment with PIAS3. These data suggest the ther- apeutic potential of PIAS3 in the development of aGVHD through reciprocal regulation of Th17/Treg lineages. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy with proven efficacy for the management of many hematologic malignant diseases and bone marrow failure. Allogeneic HSCT is clearly indicated for severe immunodeficien- cies that are lethal in the first few years of life. However, its wide ∗ Corresponding author at: Department of Life Science, College of Medicine, Lab- oratory of Immune Network, Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea. Tel.: +82 2 2258 7467; fax: +82 2 599 4287. E-mail address: iammila@catholic.ac.kr (M.-L. Cho). application is hampered by the development of graft-versus-host disease (GVHD) [1]. The development of GVHD requires escalated and prolonged immunosuppressive therapy that increases the risk of infectious complications and, ultimately, mortalities in HSCT recipients. Despite advances in the development of prophylaxis agents, acute GVHD (aGVHD; grades II–IV) occurs in 30–60% of patients after allogeneic HSCT from HLA-identical sibling donors [2]. Prevention of GVHD has been the major challenge of allogeneic HSCT. Although the pathogenesis of aGVHD remains unresolved thus far, its development is considered to be caused by mature donor T cells that recognize genetically disparate recipient antigens on APCs, resulting in the destruction of GVHD target organs, includ- ing the skin, liver, lung, and gastrointestinal tract [3,4].aGVHD is a proinflammatory process, the pathophysiology of which is http://dx.doi.org/10.1016/j.imlet.2014.03.014 0165-2478/© 2014 Elsevier B.V. All rights reserved.