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Human TIGIT on Porcine Aortic Endothelial Cells Suppresses Immunobiology 224 (2019) 605–613 Contents lists available at ScienceDirect Immunobiology journal homepage: www.elsevier.com/locate/imbio Human TIGIT on porcine aortic endothelial cells suppresses xenogeneic macrophage-mediated cytotoxicity T ⁎ Yuki Noguchia, Akira Maedaa, , Pei-Chi Loa, Chihiro Takakuraa, Tomoko Hanedaa, Tasuku Kodamaa, Tomohisa Yoneyamaa, Chiyoshi Toyamaa, Yuko Tazukea, Hiroomi Okuyamaa, Shuji Miyagawaa,b a Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan b Meiji University International Institute for Bio-Resource Research, Kanagawa, Japan ARTICLE INFO ABSTRACT Keywords: Purpose: The delayed rejection caused by strong cell-mediated innate and adaptive xenogeneic immune re- Xenotransplantation sponses continues to be a major obstacle. Pig-to-Human Therefore, suppressing macrophage function could be effective in avoiding this type of rejection. In this study, Macrophage the suppression of T-cell immunoglobulin and ITIM domain (TIGIT) function against macrophage-mediated TIGIT xenogeneic rejection was investigated. Material and methods: Naïve porcine aortic endothelial cell (PAEC) and PAEC transfectant with TIGIT (PAEC/ TIGIT) were co-cultured with M1 macrophages, and the degree of cytotoxicity was determined by a counting beads assay. The anti/pro-inflammatory gene expression was determined by RT-PCR and the phosphorylated SHP-1 in the macrophages after co-culturing with PAEC or PAEC/TIGIT was evaluated by western blotting. Results: CD155 was expressed at essentially equal levels on both M1 and M2 macrophages, whereas TIGIT was highly expressed on M2 macrophages but not in M1 macrophages. TIGIT on PAEC significantly reduced the cytotoxicity of M1 macrophages but no significant suppression of phagocytosis was detected. TIGIT also caused a decrease in the expression of pro-inflammatory cytokines, namely TNFα, IL-1β and IL-12 in M1 macrophages. Furthermore, PAEC/TIGIT caused a significant increase in phosphorylated SHP-1 in M1 macrophages compared to PAEC. Conclusion: The findings of this study indicate that TIGIT suppresses xenogeneic M1 macrophage-induced cy- totoxicity, probably at least in part, via the phosphorylation of SHP-1. In addition, the reduced expression of some pro-inflammatory cytokines, namely TNFα, IL-1β and IL-12, was observed in M1 macrophages that had been cultured with PAEC/TIGIT. 1. Introduction focus is on NK cells because xenografts has been believed to be more susceptible to these cells due to the lack of inhibitory signals to human Xenografts typically show a more severe immune reaction from the NK cells caused by MHC (SLA) class Ⅰ incompatibility. It has, in fact, recipient than allografts because of species differences. However, with been shown that the ectopic expression of human MHC class Ⅰ mole- the advent of pigs lacking Gal α 1,3 Gal and overexpressing human cules on porcine cells reduces NK cell-induced xenocytotoxicity complement regulatory proteins, the hurdle of hyperacute rejection has (Matsunami et al., 2002; Forte et al., 2005; Lilienfeld et al., 2007; largely been overcome (Ekser et al., 2012; Klymiuk et al., 2009; Matsunami et al., 2008; Yung et al., 2018; Abicht et al., 2018). How- Miyagawa et al., 2010, 2015). On the other hand, the delayed xenograft ever, macrophages are thought to be much more important than NK rejection caused by strong cell-mediated innate and adaptive xeno- cells because they are responsible, not only for being an important geneic immune responses continues to be a major obstacle (Scalea player in innate immunity and priming T cells as a bridge from innate to et al., 2012; Schneider and Seebach, 2008). Among such cells, the first adaptive immunity, but also are the primary effector cells in xenograft Abbreviations: cDNA, complementary deoxyribonucleic acid; PAEC, porcine aortic endothelial cell; GM-CSF, Granulocyte-macrophage colony-stimulating factor; MHC, major histocompatibility complex; SLA, Swine leukocyte antigen; RNA, ribonucleic acid; RT-PCR, reverse transcription - polymerase chain reaction ⁎ Corresponding author at: Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. E-mail address: [email protected] (A. Maeda). https://doi.org/10.1016/j.imbio.2019.07.008 Received 25 April 2019; Received in revised form 3 July 2019; Accepted 30 July 2019 Available online 03 August 2019 0171-2985/ © 2019 Elsevier GmbH. All rights reserved. Y. Noguchi, et al. Immunobiology 224 (2019) 605–613 rejection (Fox et al., 2001). In fact, some reports have shown that suppressive function of TIGIT exerts a similar immunomodulatory macrophages are dominantly infiltrating in rejected xenografts (Appels function on macrophages in an in vitro pig-to-human xenograft model. et al., 1989; Schwizer et al., 1984), suggesting that they are involved in the pathogenesis of delayed xenograft rejection. Therefore, the sup- 2. Materials & methods pression of macrophage function would be predicted to be quite ef- fective in terms of avoiding cell-mediated delayed rejection. 2.1. Cells Both of these cell-mediated innate and adaptive immunity pro- cesses, several receptors related to the activation of these cells contain A porcine aortic endothelial cell (PAEC) line was maintained in cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAM) Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% and the signals induced by ITAM are regulated by other receptors with heat-inactivated fetal bovine serum (FBS). immunoreceptor tyrosine-based inhibitory motifs (ITIM) (Veillette et al., 2002). However, it would be impossible for wild porcine cells to 2.2. Plasmid construction interact with these inhibitory receptors on human immune cells be- cause they do not produce the ligands that are needed. Consequently, cDNA for human TIGIT without its intracellular inhibitory motif the transgene of human ligands for these inhibitory receptors in pigs (Gene Bank No. EU675310.1) was synthesized by Japan Integrated represents an excellent strategy to inhibit macrophage-mediated im- DNA Technologies (Tokyo, Japan). The construct was cloned into the mune responses in pig-to-human xenotransplantation. ITIM-dependent pCXN2L expression vector, followed by checking by an ABI 310 se- inhibitory receptors and their respective ligands, such as SIRPα-CD47 quencer (Applied Biosystems, Waltham, MA, USA). The plasmid was or the Surfactant protein D (SP-D), actually have been demonstrated to amplified and isolated using standard techniques after transformation play a role in controlling the phagocytosis that is mediated by macro- into Escherichia coliDh5α. phages (Barclay and Brown, 2006; Ide et al., 2007; Jiaravuthisan et al., 2018). However, CD47 has also been reported to inhibit eNOS and 2.3. Preparation of PAEC transfectant by lipofection VEGF activity and to suppress the survival of endothelial cells from cellular stress via binding to TSP-1 (Schwartz et al., 1993; Ramanathan Five microgram plasmid was mixed with 40 μl Lipofectamine 2000™ et al., 2011; Wang and Yang, 2012; Martinelli et al., 2013; Sharifi- reagent (Thermo Fisher Scientific, Tokyo, Japan) and introduced into Sanjani et al., 2014). A recent study by Chen et al. demonstrated that in PAEC. The PAEC transfectants were cultured in DMEM complete an allogeneic cardiotransplant model, the elimination of CD47 from medium for 24 h in 5% CO2 at 37 °C. The cells were selected by cul- donor grafts induced long term survival (Chen et al., 2019). These turing in complete medium with 800 μg/mL G418 (Thermo Fisher findings suggest that the effect of CD47 in vascularized xenograft needs Scientific, Tokyo, Japan). The PAEC expressing TIGIT (PAEC/TIGIT) to be given more consideration. Furthermore, because other candidates used in this study was isolated by magnetic beads sorting after G418 such as HLA-E (Maeda et al., 2013) and G1 (Esquivel et al., 2015) also selection. bind, not only to inhibitory receptors, but also activation receptors, in previous studies gene modification was required to induce a greater 2.4. Generation of M1 and M2 macrophages inhibitory function (Matsunami et al., 2002, 2006). These findings in- dicate that the appearance of a new candidate is an important subject in Human peripheral blood mononuclear cells (PBMCs) were obtained terms of suppressing macrophage-mediated xenogeneic rejection. from healthy volunteer donors using lymphocyte isolation solution The T-cell immunoglobulin and ITIM domain, TIGIT, was first re- (Nakarai Tesque, Kyoto, Japan). Human monocytes were isolated by a ported to inhibit the activation of NK cell and T cell as an immune plastic adherence method. To generate M1 macrophages, human blood checkpoint (Stanietsky et al., 2009; Yu et al., 2009). TIGIT consists of monocytes were cultured in the presence of 100 ng/ml rGM-CSF four domains, as follows: an IgV domain, a transmembrane domain, an (Peprotech, Rocky Hill, NJ, USA). Five days after, cells were harvested immunoreceptor tyrosine-based inhibitory motif (ITIM) and an Ig tail- and purified with negative selection using Pan Monocyte Isolation Kit, tyrosine (ITT)-like motif (Levin et al., 2011; Yu et al., 2009), and has a human (Miltenyi Biotec Inc., Bergisch Gladbach, Germany). The nega- competitive relationship with the immune activation receptor CD226 or tive cells were used as M1 macrophages. M2 macrophages were de- the DNAX accessory molecule-1 (DNAM-1) for CD155 (PVR or the po- veloped by culturing in the presence of 100 ng/ml rM-CSF (R&D liovirus
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