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BTLA−HVEM Checkpoint Axis Regulates Hepatic Homeostasis and Inflammation in a Cona-Induced Hepatitis Model in Zebrafish

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BTLA−HVEM Checkpoint Axis Regulates Hepatic Homeostasis and Inflammation in a Cona-Induced Hepatitis Model in Zebrafish BTLA−HVEM Checkpoint Axis Regulates Hepatic Homeostasis and Inflammation in a ConA-Induced Hepatitis Model in Zebrafish This information is current as Wei Shi, Tong Shao, Jiang-yuan Li, Dong-dong Fan, Ai-fu of September 27, 2021. Lin, Li-xin Xiang and Jian-zhong Shao J Immunol published online 27 September 2019 http://www.jimmunol.org/content/early/2019/09/26/jimmun ol.1900458 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/09/26/jimmunol.190045 Material 8.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 27, 2019, doi:10.4049/jimmunol.1900458 The Journal of Immunology BTLA–HVEM Checkpoint Axis Regulates Hepatic Homeostasis and Inflammation in a ConA-Induced Hepatitis Model in Zebrafish Wei Shi,* Tong Shao,* Jiang-yuan Li,* Dong-dong Fan,* Ai-fu Lin,* Li-xin Xiang,* and Jian-zhong Shao*,† The BTLA2HVEM checkpoint axis plays extensive roles in immunomodulation and diseases, including cancer and autoimmune disorders. However, the functions of this checkpoint axis in hepatitis remain limited. In this study, we explored the regulatory role of the Btla–Hvem axis in a ConA-induced hepatitis model in zebrafish. Results showed that Btla and Hvem were differentially expressed on intrahepatic Cd8+ T cells and hepatocytes. Knockdown of Btla or Hvem significantly promoted hepatic inflamma- + tion. Btla was highly expressed in Cd8 T cells in healthy liver but was downregulated in inflamed liver, as evidenced by a Downloaded from disparate proportion of Cd8+Btla+ and Cd8+Btla– T cells in individuals without or with ConA stimulation. Cd8+Btla+ T cells showed minimal cytotoxicity to hepatocytes, whereas Cd8+Btla– T cells were strongly reactive. The depletion of Cd8+Btla– T cells reduced hepatitis, whereas their transfer enhanced hepatic inflammation. These observations indicate that Btla endowed Cd8+Btla+ T cells with self-tolerance, thereby preventing them from attacking hepatocytes. Btla downregulation deprived this tolerization. Mechanistically, Btla–Hvem interaction contributed to Cd8+Btla+ T cell tolerization, which was impaired by Hvem + – knockdown but rescued by soluble Hvem protein administration. Notably, Light was markedly upregulated on Cd8 Btla T cells, http://www.jimmunol.org/ accompanied by the transition of Cd8+Btla+Light– to Cd8+Btla–Light+ T cells during hepatitis, which could be modulated by Cd4+ T cells. Light blockade attenuated hepatitis, thereby suggesting the positive role of Light in hepatic inflammation. These findings provide insights into a previously unrecognized Btla–Hvem–Light regulatory network in hepatic homeostasis and inflammation, thus adding a new potential therapeutic intervention for hepatitis. The Journal of Immunology, 2019, 203: 000–000. cell activation is strictly regulated by numerous costim- CTL-associated protein 4 (CTLA-4) in humans. This ligand is ulatory and coinhibitory molecules that comprise diverse a type I membrane glycoprotein that contains a type V Ig domain T immune checkpoint axes of adaptive immunity (1). These in its extracellular region and three functional tyrosine residues by guest on September 27, 2021 immune checkpoint axes are crucial for self-tolerance, which (Tyrs) embedded in one growth factor receptor–bound protein 2 prevents the immune system from indiscriminately attacking cells (Grb2) binding site and two immunoreceptor tyrosine-based mo- to maintain homeostasis (2, 3). The dysregulation of immune tifs in its cytoplasmic tail, which are essential for the recruitment checkpoint axes leads to various diseases, including cancer, in- of Grb2 and Src homology phosphatase-1/-2 (6). HVEM is a flammation, and autoimmune disorders (4, 5). Among the growing member of the TNFR superfamily and is a type I membrane family of checkpoint inhibitors, the B and T lymphocyte attenu- protein with an N terminus extracellular region and a cytoplas- ator (BTLA), which is associated with the herpesvirus entry me- mic segment closely associated with TNFR-associated factors diator (HVEM), is a promising target for immunotherapy because (TRAFs) and STAT3 signaling pathways (8–10). The ectodomain of its great potential use in multiple types of cancer and other of HVEM is composed of four cysteine-rich domains (CRDs). diseases (5–7). CRD1 is combined with BTLA and CD160, whereas CRD2 and BTLA is an Ig superfamily member that mainly serves as a CRD3 are mainly responsible for recognizing lymphotoxin-a and coinhibitor similar to programmed cell death 1 (PD-1) and LIGHT (lymphotoxin, exhibits inducible expression and competes *Key Laboratory for Cell and Gene Engineering of Zhejiang Province, College of Address correspondence and reprint requests to Prof. Jian-zhong Shao and Associate Prof. Life Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China; Li-xin Xiang, College of Life Sciences, Zhejiang University, 866 YuHangTang Road, and †Laboratory for Marine Biology and Biotechnology, Qingdao National Labora- Hangzhou 310058, People’s Republic of China. E-mail addresses: [email protected] tory for Marine Science and Technology, Qingdao 266071, People’s Republic of (J.-z.S.) and [email protected] (L.-x.X.) China The online version of this article contains supplemental material. ORCIDs: 0000-0002-2236-4708 (W.S.); 0000-0003-3020-6264 (T.S.). Abbreviations used in this article: ALT, alanine aminotransferase; AST, aspartate Received for publication April 24, 2019. Accepted for publication August 29, 2019. aminotransferase; Bcl-2, B cell lymphoma 2; BHMT, Bhmt, betaine homocysteine S-methyltransferase; BTLA, Btla, B and T lymphocyte attenuator; Co-IP, coimmu- This work was supported by grants from the National Natural Science Foundation of noprecipitation; CRD, cysteine-rich domain; CsA, cyclosporin A; EGFP, enhanced China (31630083, 31572641), the National Key Research and Development Program GFP; Fasl, Fas ligand; FCM, flow cytometry; Grb2, growth factor receptor–bound of China (2018YFD0900503, 2018YFD0900505, 2016YFA0101001), the Open Fund protein 2; HVEM, Hvem, herpesvirus entry mediator; Lamp-1, lysosomal-associated of the Laboratory for Marine Biology and Biotechnology, the Qingdao National membrane protein 1; Lck, lymphocyte protein tyrosine kinase; LIGHT, Light, lym- Laboratory for Marine Science and Technology, Qingdao, China (OF2017NO02), photoxin, exhibits inducible expression and competes with HSV glycoprotein D for the Open Funding Project of the State Key Laboratory of Bioreactor Engineering, herpesvirus entry mediator; LV, lentivirus; mLIGHT, membrane-bound LIGHT; PFA, and the Zhejiang Major Special Program of Breeding (2016C02055-4). paraformaldehyde; qRT-PCR, quantitative real-time PCR; sBtla, soluble Btla; The sequences presented in this article have been submitted to GenBank (http://www. shRNA, short hairpin RNA; siRNA, small interfering RNA; sLIGHT, soluble LIGHT; ncbi.nlm.nih.gov/genbank/) under accession numbers MK112054, MK112055, and TRAF, TNFR-associated factor; TU, transducing unit. MK112056. Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900458 2 REGULATION OF BTLA–HVEM AXIS IN HEPATIC INFLAMMATION with HSV glycoprotein D for herpesvirus entry mediator, a receptor interaction by upregulated Light on Cd8+ T cells activates the expressed on T cells) (11–13). BTLA is predominantly expressed cytotoxicity of Cd8+ T cells, thereby leading to the disruption of in B cells and various T cells, including Th1, Tfh, Th17, gd T, and liver homeostasis and occurrence of hepatitis. These findings NKT cells (14–16). HVEM is extensively expressed in dendritic suggest the importance of the Btla–Hvem axis and Btla–Hvem– cells, epithelial cells, hematopoietic cells, B lymphocytes, and Light network in the liver and reveal a previously unrecognized hepatoma cells (12, 17, 18). The engagement of BTLA by HVEM mechanism underlying hepatic homeostasis and inflammation. triggers the inhibitory activity of the former on T and B cell ac- tivation by decreasing the accumulation of phosphorylated TCR and BCR signals. This occurrence leads to the tolerance or anergy Materials and Methods of CD4+ T and CD8+ T cells and inhibition of cytokine release of Experimental fish NKT cells to avoid excessive inflammatory reactions and tissue One-year-old wild-type AB zebrafish (D. rerio) with body weight of injury (19–21). The BTLA–HVEM interaction can be regulated by 0.5–1.0 g were raised and maintained at 28˚C on a 12 h/12 h light/dark LIGHT, the latter of which is also known as TNF superfamily cycle in a standard circulating system, as previously described (39). All fish used in experiments were siblings generated after
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