GRIM19 ameliorates acute graft-versus-host disease (GVHD) by modulating Th17 and Treg cell balance through down-regulation of STAT3 and NF-AT activation

Journal of Translational Medicine

Research

Eun-Kyung Kim¹  Sung-Hee Lee¹  Min-Jung Park¹  Eun Jung Lee¹  Young-Mee Moon¹  Seung Hoon Lee¹  Mi- La Cho² 

[1]The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea

[2]The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea

[3]Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, 137-040, Seoul, South Korea

[4]Conversant Research Consortium in Immunologic Disease, College of Medicine, The Catholic University of Korea, Korea 505 Banpo-Dong, Seocho-Ku, 137-040, Seoul, Korea

关键词: Th17 Cell;    Treg Cell;    Graft Versus Host Disease;    Th17 Cell Differentiation;    Acute Graft Versus Host Disease;   

DOI  :  10.1186/s12967-016-0963-0

 received in 2015-08-17, accepted in 2016-06-28,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundT helper (Th) 17 cells are a subset of T helper cells that express interleukin (IL)-17 and initiate the inflammatory response in autoimmune diseases. Regulatory T cells (Tregs) are a subpopulation of T cells that produce forkhead box P3 (FOXP3) and inhibit the immune response. Graft versus host disease (GVHD) is a complication of allogeneic tissue transplantation, and Th17 cells and their proinflammatory activity play a central role in the pathogenesis of GVHD. Gene associated with retinoid-interferon-induced mortality (GRIM) 19, originally identified as a nuclear protein, is expressed ubiquitously in various human tissues and regulate signal transducer and activator of transcription (STAT)3 activity.MethodsSplenoytes and bone marrow cells were transplanted into mice with GVHD. The alloresponse of T cells and GVHD clinical score was measured. Realtime-polymerase chain reaction (realtime-PCR) was used to examine mRNA level. Flow cytometry and enzyme linked immunosorbent assay (ELISA) was used to evaluate protein expression.ResultsA GRIM19 transgenic cell transplant inhibited Th17 cell differentiation, alloreactive T cell responses, and STAT3 expression in mice with GVHD. On the other hand, the differentiation of Tregs and STAT5 production were enhanced by GRIM19. Overall, the severity of GVHD was decreased in mice that had received GRIM19 transgenic bone marrow and spleen transplants. Transplantation from GRIM19-overexpressing cells downregulated the expression of nuclear factor of activated T cells (NFATc1) but promoted the expression of regulator of calcineurin (RCAN)3 while downregulating NFAT-dependent cytokine gene expression. This complex mechanism underlies the therapeutic effect of GRIM19.ConclusionsWe observed that GRIM19 can reduce Th17 cell differentiation and alloreactive T cell responses in vitro and in vivo. Additionally, GRIM19 suppressed the severity of GVHD by modulating STAT3 activity and controlling Th17 and Treg cell differentiation. These results suggest that GRIM19 attenuates acute GVHD through the inhibition of the excessive inflammatory response mediated by T cell activation.

【 授权许可】

CC BY   
© The Author(s) 2016