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• W2289146513 abstract "Effector T cell function rather than survival determines extent and duration of hepatitis in miceJournal of HepatologyVol. 64Issue 6PreviewAcute liver injury has a variety of causes, but is often initiated by an immune response triggered by hepatotropic viruses and other pathogens targeting this organ. A robust and sustained immune response involving both innate and adaptive immunity is critical to clear infections by viruses targeting the liver, such as the hepatitis B (HBV) [1] and C viruses (HCV) [2]. Antiviral cytotoxic CD8 T lymphocytes (CTLs) play a crucial role in mediating liver injury during infection, and the induction and maintenance of broad vigorous virus-specific CD8 T cell responses is a positive predictor of spontaneous resolution of HCV infection [3–5]. Full-Text PDF T cells play an important role in the immunological control of pathogens and tumors. CD8+ T cells scan cell surfaces with their T cell receptors for the presence of non-self antigens (originated from viruses, intracellular bacterial or from modified self antigens present in malignancies) bound to MHC-class I molecules. Specific recognition triggers T cell activation and results in the lysis of infected or tumor cells. The efficiency at which this occurs is extremely high such that a functional effector CD8+ T cell can be activated upon recognition of very few MHC-class I/non-self peptides present on the surface of the cells and can kill multiple targets [[1]Sykulev Y. Joo M. Vturina I. Tsomides T.J. Eisen H.N. Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response.Immunity. 1996; 4: 565-571Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar]. The ability of T cells to access tissues typically requires multiple steps of T cell extravasation/migration that are regulated by the expression of specific adhesion and homing molecules [[2]Iannacone M. Hepatic effector CD8(+) T-cell dynamics.Cell Mol Immunol. 2015; 12: 269-272Crossref Scopus (11) Google Scholar]. However, such a process is not strictly necessary in the liver where the lack of a continuum basal membrane separating the blood from the hepatic parenchyma allows direct T cell scanning of target cells through the fenestrated liver sinusoidal endothelial cells [[2]Iannacone M. Hepatic effector CD8(+) T-cell dynamics.Cell Mol Immunol. 2015; 12: 269-272Crossref Scopus (11) Google Scholar]. Since the liver is an organ indispensable for life, the easy accessibility of CD8+ T cells to hepatocytes has been balanced by additional levels of control of intrahepatic CD8+ T cell function to avoid that immunological control of pathogens result in the self-destruction of the organ. The elegant paper from the group of Bowen and Bertolino published in this issue of the Journal of Hepatology [[3]Bertolino P. et al.The extent and duration of acute hepatitis in mice is dominated by the function rather than by the survival of effector CD8 T cells.J Hepatol. 2016; 64: 1327-1338Abstract Full Text Full Text PDF Scopus (4) Google Scholar] directly investigates this problem and analyzes the mechanisms underlying the control of CD8+ T cell mediated liver damage. The authors used the Met-Kb transgenic mouse model in which liver damage is induced by the transfer of transgenic T cells that recognize a self antigen presented by MHC-class I H-2 Kb, expressed only in the liver and in lymph-nodes and they ask whether the most important parameter controlling liver damage is the survival or the cytokine-producing and lytic activity of T cells. To address this question they adoptively transfer in mic,e two types of alloreactive T cells that lack either a gene that regulates T cell survival (BIM-deficient- thus resistant to apoptosis) or one that regulates T cell function (SOCS-1, suppressor of cytokine signaling 1 deficient). As expected, BIM-deficient T cells display increased survival capacity and thus are present in increased numbers in the intrahepatic environment in comparison to normal T cells. However, the increased numbers of alloreactive T cells in the liver have a negligible effect on acute liver damage and do not lead to chronic liver inflammation. In contrast, the transfer of SOCS-1-deficient T cells causes a more severe and slightly prolonged hepatitis but again does not result in the development of chronic liver inflammation. Indeed, wild-type, BIM−/− or SOCS-1−/− T cells became functionally exhausted upon interaction with high levels of their cognate antigen in the liver within 5–7 days after adoptive transfer. Thus, this work provides a demonstration that an important parameter that determines the extent of liver cell damage during acute hepatitis is the initial functional property of the CD8+ T cells. This finding is not unexpected: it seems logical that CD8+ T cells (SOCS-1 deficient) that possess a higher intrinsic ability to directly kill hepatocytes and produce inflammatory cytokines (such as TNF-α) will cause higher levels of liver damage as compared to equal number of less fit T cells. These findings also confirm the observation that liver damage in acute or chronically virus-infected livers is not directly proportional to the frequency of virus-specific T cells but depends on the functional capacity of these cells [[4]Maini M.K. Boni C. Lee C.K. Larrubia J.R. Reignat S. Ogg G.S. et al.The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.J Exp Med. 2000; 191: 1269-1280Crossref PubMed Scopus (682) Google Scholar]. However, what is striking and somehow surprising is the similar and rapid kinetics at which intrahepatic T cells with different effector capacities are functionally exhausted and the extent of their functional silencing in a liver that constitutively presents high dose of the T cell cognate antigen. T cells that enter the liver appear to lose their functionality within a few days upon adoptive transfer (5–7 days). The functional exhaustion of the transgenic T cells is observed preferentially in the intrahepatic environment as T cells present in the lymphonodes maintain a degree of function ability. These findings nicely complement the recent demonstration of the same group that the quantity of antigen expressed by the hepatocytes in the liver is the major determinant of the functional fate of CD8+ T cells [[5]Tay S.S. Wong Y.C. McDonald D.M. Wood N.A.W. Roediger B. Sierro F. et al.Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses.Proc Natl Acad Sci U S A. 2014; 111: E2540-E2549Crossref PubMed Scopus (70) Google Scholar] even though what we are still missing is the exact mechanisms of the intrahepatic T cell functional silencing. The authors argued that T cell exhaustion is likely mediated by the upregulation of different co-inhibitory molecules like PD-1 and TIM-3. Functionally exhausted T cells present in the liver of these mice overexpressed these two co-inhibithory molecules. However, T cell functional exhaustion was not only mediated by PD-1 engagement since treatment with anti-PD-L1 antibody was not sufficient to restore a hepatic immune response. It is possible that the rapid silencing of T cell functionality in the liver observed few days after adoptive transfer could have be at least partially caused by metabolic changes in the inflamed intrahepatic environment. Arginase which is known to be released by dying hepatocytes [[6]Chisari F.V. Nakamura M. Milich D.R. Han K. Molden D. Leroux-Roels G.G. Production of two distinct and independent hepatic immunoregulatory molecules by the perfused rat liver.Hepatology. 1985; 5: 735-743Crossref PubMed Scopus (19) Google Scholar], has been shown to dampen T cell function during acute [[7]Sandalova E. Laccabue D. Boni C. Watanabe T. Tan A. Zong H.Z. et al.Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells.Gastroenterology. 2012; 143e3Abstract Full Text Full Text PDF Scopus (57) Google Scholar] and chronic [[8]Das A. Hoare M. Davies N. Lopes A.R. Dunn C. Kennedy P.T.F. et al.Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection.J Exp Med. 2008; 205: 2111-2124Crossref PubMed Scopus (194) Google Scholar] hepatitis through the removal of the amino acid (arginine) essential for T cell function. However, such mechanism which is associated with the presence of liver inflammation, does not explain the prolonged suppression of T cell function observed in these animals after the resolution of liver damage. Despite the absence of any signs of chronic liver inflammation, the T cells that persist in the liver of the treated mice (present in very large numbers when the authors adoptively transfer BIM-deficient T cells) maintain a profound functionally exhausted phenotype as they lack any lytic or cytokine-producing abilities and they are refractory to treatment with anti-PD-L1. It will be interesting to test whether the observed intrahepatic T cell exhaustion is caused by other T cell-intrinsic functional parameters, such as expression of other inhibitory molecules (CTLA4, TGIT) or T cell receptor downregulation, mechanisms which are likely to occur in the presence of the high doses of antigen observed in the liver of these mice. Exhausted T cells in chronically infected livers express more than a single co-inhibitory molecule [9Nakamoto N. Cho H. Shaked A. Olthoff K. Valiga M.E. Kaminski M. et al.Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade.PLoS Pathog. 2009; 5e1000313Crossref PubMed Scopus (297) Google Scholar, 10Schurich A. Khanna P. Lopes A.R. Han K.J. Peppa D. Micco L. et al.Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection.Hepatology. 2011; 53: 1494-1503Crossref PubMed Scopus (241) Google Scholar, 11Golden-Mason L. Palmer B.E. Kassam N. Townshend-Bulson L. Livingston S. McMahon B.J. et al.Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells.J Virol. 2009; 83: 9122-9130Crossref PubMed Scopus (364) Google Scholar]. Nevertheless, a different, although not mutually exclusive possibility is that the maintenance of T cell silencing is mediated by other immune regulatory networks, like regulatory T cells [[12]Xu D. Fu J. Jin L. Zhang H. Zhou C. Zou Z. et al.Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B.J Immunol. 2006; 177: 739-747Crossref PubMed Scopus (388) Google Scholar] or granulocytic myeloid suppressor cells that were recently shown to be present in high numbers in the intrahepatic environment of patients with chronic hepatitis B and low/absence level of liver pathology [[13]Pallett L.J. Gill U.S. Quaglia A. Sinclair L.V. Jover-Cobos M. Schurich A. et al.Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells.Nat Med. 2015; 21: 591-600Crossref PubMed Scopus (187) Google Scholar]. Evaluation of the contribution of these different factors will be important to understand whether a recovery of intrahepatic T cell function in liver pathologies characterized by persistent and high expression of non-self antigens, (chronic viral hepatitis, hepatocellular carcinoma) would always necessitate a reduction in the number of antigen expressing hepatocytes or whether strategies designed only to alter the liver microenvironment (for example with Toll-like receptors mediated stimulation) might have an effect. Certainly as the authors pointed out in their discussion, the data presented in their study is relevant for immunological therapies that attempt to restore T cell effector function both in patients chronically infected with hepatotropic viruses or in liver cancer. Despite the success of anti-PD-1 treatment for the restoration of intra-heaptic T cell function in vitro [[14]Fisicaro P. Valdatta C. Massari M. Loggi E. Biasini E. Sacchelli L. et al.Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B.Gastroenterology. 2010; 138: 682-684Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar] and in chimps [[15]Fuller M.J. Callendret B. Zhu B. Freeman G.J. Hasselschwert D.L. Satterfield W. et al.Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).Proc Natl Acad Sci U S A. 2013; 110: 15001-15006Crossref PubMed Scopus (139) Google Scholar], the ineffectiveness of such treatment in this mouse model questions its therapeutic potential in patients with HCC or chronic viral hepatitis, a concept further supported by the modest results of anti-PD-1 clinical trial in HCV-infected subjects [[16]Gardiner D. Lalezari J. Lawitz E. DiMicco M. Ghalib R. Reddy K.R. et al.A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.PLoS One. 2013; 8e63818Crossref PubMed Scopus (186) Google Scholar]. The prospect of immunotherapy on these liver pathologies appears even more daunting if we consider that T cell exhaustion was observed here in mice with relatively normal livers, where T cell access and function is not constrained by anatomical barriers [[17]Guidotti L.G. Inverso D. Sironi L. Di Lucia P. Fioravanti J. Ganzer L. et al.Immunosurveillance of the liver by intravascular effector CD8(+) T cells.Cell. 2015; 161: 486-500Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar] and by the suppressive immune environment present in livers with chronic inflammation (reviewed in [[18]Bertoletti A. Ferrari C. Adaptive immunity HBV infection.J Hepatol. 2016; 64: S71-S83Abstract Full Text Full Text PDF Scopus (274) Google Scholar]). On the other hand, the demonstration that hepatocytes are so well protected against T cell mediated immunological damage could be seen as an incentive to test new approaches of immunotherapy like transfer of gene-modified T cells or that combine check point inhibitors with agents that modify antigen expression in liver cells and T cell induction [[19]Bertoletti A. Rivino L. Hepatitis B: future curative strategies.Curr Opin Infect Dis. 2014; 27: 528-534Crossref PubMed Scopus (26) Google Scholar]. An approach combining therapeutic vaccination with anti-PD-L1 and antiviral therapies was shown to be effective in woodchucks chronically infected with woodchucks hepatitis virus [[20]Liu J. Zhang E. Ma Z. Wu W. Kosinska A. Zhang X. et al.Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection.PLoS Pathog. 2014; 10e1003856Crossref PubMed Scopus (182) Google Scholar]. This study shows that T cells struggle to maintain their fitness in the liver environment and help on multiple fronts may be needed for them to do so. This work was supported by a Singapore Translational Research (STaR) Investigator Award (NMRC/STaR/013/2012) to A.B. AB collaborates and receives research support from Gilead Sciences to test the effect of HBV antigens on immune cell function. He has acted as a consultant and served on the advisory boards of Gilead Sciences, Janssen-Cilag, Medimmune, IONIS and Abivax. AB is also a co-founder of LION TCR pte. ltd.; a biotech company developing T cell receptors for treatment of virus-related cancers and chronic viral diseases." @default.
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• W2289146513 title "T cell fitness in the liver: How can T cells keep it up?" @default.
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• W2289146513 cites W1983251878 @default.
• W2289146513 cites W1992541741 @default.
• W2289146513 cites W1998048927 @default.
• W2289146513 cites W1999770898 @default.
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• W2289146513 cites W2033239466 @default.
• W2289146513 cites W2051634508 @default.
• W2289146513 cites W2056052081 @default.
• W2289146513 cites W2068907790 @default.
• W2289146513 cites W2077940506 @default.
• W2289146513 cites W2092846101 @default.
• W2289146513 cites W2116118057 @default.
• W2289146513 cites W2117117966 @default.
• W2289146513 cites W2167550756 @default.
• W2289146513 cites W2168231169 @default.
• W2289146513 cites W2333436982 @default.
• W2289146513 cites W2337204897 @default.
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