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Haematologica 2020 Volume 105(1):226-234
Stem Cell Transplantation
Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease
Satomi Matsuoka,1 Daigo Hashimoto,1 Masanori Kadowaki,2
Hiroyuki Ohigashi,1 Eiko Hayase,1 Emi Yokoyama,1 Yuta Hasegawa,1
Takahiro Tateno,1 Xuanzhong Chen,1 Kazutoshi Aoyama,2 Hideyo Oka,2 Masahiro Onozawa,1 Kiyoshi Takeda,3 Koichi Akashi2 and Takanori Teshima1
1Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo; 2Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka and 3Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
ABSTRACT
Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin- 1 receptor superfamily to the NFkB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/interleukin-1 receptor-associated kinase 4 path- way plays an important role, not only in innate immunity, but also T-cell immunity; however, its role in donor T cells on the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allo- geneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly amelio- rated GvHD after allo-SCT. These results thus demonstrate that donor T- cell MyD88/ interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT.
Introduction
Myeloid differentiation factor 88 (MyD88) is a critical adaptor molecule to trans- duce the signals through receptors belonging to most of the TLR and IL-1R family (TLR/IL-1R superfamily) to NFkB pathway and inflammasome by recruiting IL-1R- associated kinase 4 (IRAK4).1 The TLR/MyD88 pathway in myeloid cells plays an essential role in innate immunity by recognizing pathogen-associated molecular patterns (PAMP) released by microbes and damage-associated molecular patterns (DAMP) produced by stressed or dying cells.2 MyD88 dependent signaling in myeloid cells plays proinflammatory roles by secreting proinflammatory cytokines and enhancing antigen presentation, and also homeostatic roles by maintaining reg- ulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC).3,4 In addition, there is growing evidence to indicate that MyD88 signaling in T cells also plays a critical role in T-cell proliferation, survival, and differentiation upon TCR-stimula- tion.5-13
Graft-versus-host disease (GvHD), the major complication of allogeneic hematopoietic stem cell transplantation (allo-SCT), is mediated by donor T cells recognizing host-derived alloantigens expressed on professional or non-profession- al APC and further accelerated by pre-transplant conditioning-mediated inflamma- tory milieu and tissue injury.14,15 In particular, damage of the epithelial and mucous barrier allows translocation of bacteria and its immunostimulatory molecules into systemic circulation, leading to subsequent activation of innate immune responses
Correspondence:
TAKANORI TESHIMA
teshima@med.hokudai.ac.jp
Received: August 2, 2018. Accepted: April 30, 2019. Pre-published: May 2, 2019.
doi:10.3324/haematol.2018.203380
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1/226
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