Abstract
Background
Previous studies showed that CD4+ T cells play a critical role in Con A-induced hepatitis in wild-type mice. However, the role of CD8+ T cells in the setting of Con A-induced hepatitis is enigmatic. The aim of study is to investigate the function of CD8+ T cells in the context of Con-A-induced hepatitis.
Materials and subjects
Two different mouse models of Con A-induced hepatitis, T cell-transferred Rag2−/− mice and wild-type C57BL/6 mice, were used in the present study. IL-33 gene knockout mice were used to confirm the role of alarmin in Con A-induced hepatitis.
Results
Opposing to the previous results obtained in wild-type mice, transferred CD4+ T cells alone into Rag2-knockout mice cannot cause hepatitis upon Con A challenge. In stark contrast, transferred CD8+ T cells play an important role in the pathogenesis of Con A-induced liver injury in T cell-transferred Rag2-deficient mice. Furthermore, we found that hepatocytes injured by perforin-based CD8+ T cell cytotoxicity release the alarmin IL-33. This cytokine promotes ST2+ ILC2 development and the secretion of cytokines IL-5 and IL-13 to mediate liver inflammation triggered by Con A challenge. In addition, these type 2 cytokines, including those originated from CD4+ T cells, result in eosinophils accumulation in liver to exacerbate the liver injury after Con A administration.
Conclusion
Our data for the first time revealed that CD8+ T cells play an indispensable role in the pathogenesis of Con A-induced liver injury in T cell-transferred Rag2-deficient mice. Therefore, the CD8+ T cell/IL-33/ILC2 axis is a potential therapeutic target for acute immune-mediated liver injury.
Similar content being viewed by others
References
Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 1992;90:196–203.
Mizuhara H, O’Neill E, Seki N, Ogawa T, Kusunoki C, Otsuka K, et al. T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J Exp Med. 1994;179:1529–37.
Knolle PA, Gerken G, Loser E, Dienes HP, Gantner F, Tiegs G, et al. Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice. Hepatology. 1996;24:824–9.
Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA. 2000;97:5498–503.
Tiegs G. Experimental hepatitis and role of cytokines. Acta Gastroenterol Belg. 1997;60:176–9.
Watanabe Y, Morita M, Akaike T. Concanavalin A induces perforin-mediated but not Fas-mediated hepatic injury. Hepatology. 1996;24:702–10.
Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47:729–36.
Bogdanos DP, Gao B, Gershwin ME. Liver immunology. Compr Physiol. 2013;3:567–98.
Spits H, Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol. 2012;30:647–75.
Eberl G, Colonna M, Di Santo JP, McKenzie AN. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348:aaa6566.
Zhang Y, Tang J, Tian Z, van Velkinburgh JC, Song J, Wu Y, et al. Innate lymphoid cells: a promising new regulator in fibrotic diseases. Int Rev Immunol. 2016;35:399–414.
Bernink JH, Germar K, Spits H. The role of ILC2 in pathology of type 2 inflammatory diseases. Curr Opin Immunol. 2014;31:115–20.
Huang Y, Paul WE. Inflammatory group 2 innate lymphoid cells. Int Immunol. 2016;28:23–8.
Bjorkstrom NK, Kekalainen E, Mjosberg J. Tissue-specific effector functions of innate lymphoid cells. Immunology. 2013;139:416–27.
Huang Y, Guo L, Qiu J, Chen X, Hu-Li J, Siebenlist U, et al. IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat Immunol. 2015;16:161–9.
Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011;12:21–7.
Liu M, Zhang C. The role of innate lymphoid cells in immune-mediated liver diseases. Front Immunol. 2017;8:695.
Gorski SA, Hahn YS, Braciale TJ. Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog. 2013;9:e1003615.
Nussbaum JC, Van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A, Molofsky AB, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013;502:245–8.
Arshad MI, Piquet-Pellorce C, L’Helgoualc’h A, Rauch M, Patrat-Delon S, Ezan F, et al. TRAIL but not FasL and TNFalpha, regulates IL-33 expression in murine hepatocytes during acute hepatitis. Hepatology. 2012;56:2353–62.
Carriere V, Arshad MI, Le Seyec J, Lefevre B, Farooq M, Jan A, et al. Endogenous IL-33 deficiency exacerbates liver injury and increases hepatic influx of neutrophils in acute murine viral hepatitis. Mediators Inflamm 2017;2017:1359064.
McSorley HJ, Blair NF, Smith KA, McKenzie AN, Maizels RM. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol. 2014;7:1068–78.
Le Goffic R, Arshad MI, Rauch M, L’Helgoualc’h A, Delmas B, Piquet-Pellorce C, et al. Infection with influenza virus induces IL-33 in murine lungs. Am J Respir Cell Mol Biol. 2011;45:1125–32.
Prefontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009;183:5094–103.
Arshad MI, Rauch M, L’Helgoualc’h A, Julia V, Leite-de-Moraes MC, Lucas-Clerc C, et al. NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis. Eur J Immunol. 2011;41:2341–8.
Vasanthakumar A, Kallies A. Interleukin (IL)-33 and the IL-1 family of cytokines-regulators of inflammation and tissue homeostasis. Cold Spring Harb Perspect Biol. 2017. https://doi.org/10.1101/cshperspect.a028506.
Gong Q, Zhang H, Li JH, Duan LH, Zhong S, Kong XL, et al. High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice. J Mol Med (Berl). 2010;88:1289–98.
Chen J, Duan L, Xiong A, Zhang H, Zheng F, Tan Z, et al. Blockade of IL-33 ameliorates Con A-induced hepatic injury by reducing NKT cell activation and IFN-gamma production in mice. J Mol Med (Berl). 2012;90:1505–15.
Cassim S, Raymond VA, Lapierre P, Bilodeau M. From in vivo to in vitro: Major metabolic alterations take place in hepatocytes during and following isolation. PLoS One. 2017;12:e0190366.
Moro K, Ealey KN, Kabata H, Koyasu S. Isolation and analysis of group 2 innate lymphoid cells in mice. Nat Protoc. 2015;10:792–806.
Van Dyken SJ, Mohapatra A, Nussbaum JC, Molofsky AB, Thornton EE, Ziegler SF, et al. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and gammadelta T cells. Immunity. 2014;40:414–24.
Neumann K, Karimi K, Meiners J, Voetlause R, Steinmann S, Dammermann W, et al. A proinflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis. J Immunol. 2017;198:128–37.
Kusters S, Gantner F, Kunstle G, Tiegs G. Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. Gastroenterology. 1996;111:462–71.
Louis H, Le Moine A, Flamand V, Nagy N, Quertinmont E, Paulart F, et al. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice. Gastroenterology. 2002;122:2001–10.
Duran A, Rodriguez A, Martin P, Serrano M, Flores JM, Leitges M, et al. Crosstalk between PKCzeta and the IL4/Stat6 pathway during T-cell-mediated hepatitis. EMBO J. 2004;23:4595–605.
Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10:103–10.
Villarreal DO, Weiner DB. Interleukin 33: a switch-hitting cytokine. Curr Opin Immunol. 2014;28:102–6.
Volarevic V, Mitrovic M, Milovanovic M, Zelen I, Nikolic I, Mitrovic S, et al. Protective role of IL-33/ST2 axis in Con A-induced hepatitis. J Hepatol. 2012;56:26–33.
Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A, et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci USA. 2010;107:18581–6.
Kim J, Chang DY, Lee HW, Lee H, Kim JH, Sung PS, et al. Innate-like cytotoxic function of bystander-activated CD8(+) T cells is associated with liver injury in acute hepatitis A. Immunity. 2018;48:161–73e5.
Balasiddaiah A, Davanian H, Aleman S, Pasetto A, Frelin L, Sallberg M, et al. Hepatitis C virus-specific T cell receptor mRNA-engineered human T cells: impact of antigen specificity on functional properties. J Virol. 2017;91:e00010–17.
Benechet AP, Iannacone M. Determinants of hepatic effector CD8(+) T cell dynamics. J Hepatol. 2017;66:228–33.
Doherty TA, Baum R, Newbury RO, Yang T, Dohil R, Aquino M, et al. Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis. J Allergy Clin Immunol. 2015;136:792–4.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (91542110, 81373167 to M. Fang). We thank Mr. Yong Xu and Zhihui Liang for technical assistance with flow cytometry.
Author information
Authors and Affiliations
Contributions
YZ and CQ performed the experiments. LL and SH analyzed the data. FZ and FG provided the animal model and suggestions in experimental design. YZ and MF designed the experiments, analyzed data and wrote the paper.
Corresponding author
Ethics declarations
Conflict of interest
The authors report no conflict of interest.
Additional information
Responsible Editor: Mauro Teixeira.
Rights and permissions
About this article
Cite this article
Zhang, Y., Qi, C., Li, L. et al. CD8+ T cell/IL-33/ILC2 axis exacerbates the liver injury in Con A-induced hepatitis in T cell-transferred Rag2-deficient mice. Inflamm. Res. 68, 75–91 (2019). https://doi.org/10.1007/s00011-018-1197-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00011-018-1197-9