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Inflammation Research
Published in: Inflammation Research 1/2019

01-01-2019 | Original Research Paper

CD8+ T cell/IL-33/ILC2 axis exacerbates the liver injury in Con A-induced hepatitis in T cell-transferred Rag2-deficient mice

Authors: Yuanyue Zhang, Chang Qi, Lingyun Li, Shuyao Hua, Fang Zheng, Feili Gong, Min Fang

Published in: Inflammation Research | Issue 1/2019

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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.
Literature
1.
2.
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.CrossRefPubMed
3.
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.CrossRefPubMed
4.
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.CrossRefPubMed
5.
Tiegs G. Experimental hepatitis and role of cytokines. Acta Gastroenterol Belg. 1997;60:176–9.PubMed
6.
Watanabe Y, Morita M, Akaike T. Concanavalin A induces perforin-mediated but not Fas-mediated hepatic injury. Hepatology. 1996;24:702–10.CrossRefPubMed
7.
Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47:729–36.CrossRefPubMed
8.
9.
Spits H, Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol. 2012;30:647–75.CrossRefPubMed
10.
11.
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.CrossRefPubMed
12.
Bernink JH, Germar K, Spits H. The role of ILC2 in pathology of type 2 inflammatory diseases. Curr Opin Immunol. 2014;31:115–20.CrossRefPubMed
13.
Huang Y, Paul WE. Inflammatory group 2 innate lymphoid cells. Int Immunol. 2016;28:23–8.PubMed
14.
15.
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.CrossRefPubMed
16.
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.CrossRefPubMed
17.
18.
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.CrossRefPubMedPubMedCentral
19.
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.CrossRefPubMedPubMedCentral
20.
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.CrossRefPubMed
21.
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.CrossRefPubMedPubMedCentral
22.
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.CrossRefPubMedPubMedCentral
23.
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.CrossRefPubMed
24.
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.CrossRefPubMed
25.
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.CrossRefPubMed
26.
27.
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.CrossRef
28.
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.CrossRef
29.
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.CrossRefPubMedPubMedCentral
30.
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.CrossRefPubMed
31.
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.CrossRefPubMedPubMedCentral
32.
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.CrossRefPubMed
33.
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.CrossRefPubMed
34.
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.CrossRefPubMed
35.
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.CrossRefPubMedPubMedCentral
36.
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.CrossRefPubMed
37.
38.
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.CrossRefPubMed
39.
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.CrossRefPubMed
40.
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.CrossRefPubMed
41.
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.CrossRefPubMedPubMedCentral
42.
Benechet AP, Iannacone M. Determinants of hepatic effector CD8(+) T cell dynamics. J Hepatol. 2017;66:228–33.CrossRefPubMed
43.
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.CrossRefPubMedPubMedCentral
Metadata
Title
CD8+ T cell/IL-33/ILC2 axis exacerbates the liver injury in Con A-induced hepatitis in T cell-transferred Rag2-deficient mice
Authors
Yuanyue Zhang
Chang Qi
Lingyun Li
Shuyao Hua
Fang Zheng
Feili Gong
Min Fang
Publication date
01-01-2019
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 1/2019
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-018-1197-9

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