NK Cells Cause Liver Injury and Facilitate the Induction of T Cell-Mediated Immunity to a Viral Liver Infection

Liu, Zhang–Xu; Govindarajan, Sugantha; Okamoto, Shigefumi; Dennert, Günther

doi:10.4049/jimmunol.164.12.6480

Cited by 130 publications

(140 citation statements)

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“…Again, in the mouse model during the acute phase of LCMV infection, NK cells increase in the peripheral blood by 10% over three days and NK cell margination results in a > 30% increase in the liver (McIntyre & Welsh 1986. Murine NK cells have been pheno typically characterised as NK 1.1 + TCR -, CD3 -, CD8 + , asialo + and CD16 + ; they are known to stimulate the induction of T cell-mediated immunity by secreting IFN-γ and they also cause some cell death in the liver (Liu et al 2000). In our monkey study, where NK cells are primarily CD3 -CD16 + , we did not investigate the migration of NK cells to peripheral organs, but in other published studies, we have demonstrated the presence of unidentified cellular infiltrates in the liver and lymphoid tissues (Lukashevich et al 2002(Lukashevich et al , 2003.…”

Section: Discussionmentioning

confidence: 99%

Circulating natural killer and γδ T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus

Rodas

Cairo

Djavani

et al. 2009

Mem. Inst. Oswaldo Cruz

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Rhesus macaques infected with the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) serve as a model for human infection with Lassa fever virus. To identify the earliest events of acute infection, rhesus macaques were monitored immediately after lethal infection for changes in peripheral blood mononuclear cells (PBMCs). Changes in CD3, CD4, CD8 and CD20 subsets did not vary outside the normal fluctuations of these blood cell populations; however, natural killer (NK) and γδ T cells increased slightly on day 1 and then decreased significantly after two days. The NK subsets responsible for the decrease were primarily CD3 -CD8 + or CD3 -CD16 + and not the NKT (primarily CD3 + CD56 + ) subset. Macaques infected with a non-virulent arenavirus, LCMV-Armstrong, showed a similar drop in circulating NK and γδ T cells, indicating that this is not a pathogenic event. Vγ9 T cells, representing the majority of circulating γδ T cells in rhesus macaques, displayed significant apoptosis when incubated with LCMV in cell culture; however, the low amount of cell death for virus-co-cultured NK cells was insufficient to account for the observed disappearance of this subset. Our observations in primates are similar to those seen in LCMV-infected mice, where decreased circulating NK cells were attributed to margination and cell death. Thus, the disappearance of these cells during acute hemorrhagic fever in rhesus macaques may be a cytokine-induced lymphopenia common to many virus infections. Keywords: NK cells -γδ T -rhesus macaque -LCMV -hemorrhagic feverArenaviruses are rodent-borne pathogens that have occasionally been known to cause lethal diseases in human beings (Oldstone 2002, Salvato & Rodas 2005. Every year, Lassa fever and the South American hemorrhagic fever viruses account for almost half a million cases worldwide, with approximately 16% mortality (Jahrling et al. 1985, McCormick et al. 1986, Fisher-Hoch et al. 2000. Although rodents serve as a reservoir for arenaviruses, studies of hemorrhagic fever have relied on guinea pig, hamster and primate models rather than mouse models because the disease mechanism is fundamentally different in non-reservoir species (Peters et al. 1987).Numerous murine studies of viral persistence and cell-mediated immunity have involved the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV) , Ahmed et al. 1984, Salvato et al. 1991. The WE strain of LCMV is hepatotropic in mice, guinea pigs and primates (Riviere et al. 1985, Zinkernagel et al. 1986, Lukashevich et al. 2002, but in contrast to murine LCMV infections, LCMV-WE infection of rhesus macaques can resemble Lassa hemorrhagic fever in human beings (Jahrling et al. 1980, Peters et al. 1987, Lukashevich et al. 2002. The Armstrong (ARM) strain of LCMV does not cause overt disease in monkeys, even after intravenous inoculation (Danes et al. 1963, Peters et al. 1987, Lukashevich et al. 2002.Several immunological studies have shown the importance of CD8 T lymphocytes in both protection and in induction of immuno-pathogenesis i...

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Section: Discussionmentioning

confidence: 99%

Circulating natural killer and γδ T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus

Rodas

Cairo

Djavani

et al. 2009

Mem. Inst. Oswaldo Cruz

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“…Activated hepatic NK cells are able to kill hepatocytes and induce liver injury such as viral liver infection (adenovirus), Pseudomonas aeruginosa exotoxin A (PEA) injection and carrageenan administration [9][10][11], and polyinosinic:polycytidylic acid [Poly(I:C)] injection as reported by Makoto Ochi et al and us [12,13]. Mole-cules including IFN-c, IL-12, Perforin and TRAIL contributed to NK cell cytotoxicity against hepatocytes [9,[11][12][13]. Furthermore, pre-activated T cells by a low dose of ConA could enhance the ability of Poly(I:C)-activated NK cells to cause more severe hepatocyte injury [14].…”

Section: Introductionmentioning

confidence: 99%

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Chen

Sun

Jiang

et al. 2007

Journal of Hepatology

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Background/Aims: The role of natural killer (NK) cells in the development of hepatitis B virus (HBV)-associated liver injury remains obscure. In this study, we elucidated the role of NK cells in liver injury of HBsAg transgenic mice (HBs-B6), a mimic of human healthy chronic HBsAg carriers, triggered by polyinosinic:polycytidylic acid [Poly(I:C)].Methods: HBs-B6 or wild B6 mice were intraperitoneally injected with Poly(I:C) at different doses. Liver injury was evaluated by serum transaminase activity and histopathologic changes.Results: HBs-B6 mice were over-sensitive to Poly(I:C)-induced liver injury, which was absolutely dependent on the presence of NK cells and IFN-c produced by intrahepatic NK cells. Much stronger IFN-c receptor expression was observed on hepatocytes of HBs-B6 mice, which was significantly enhanced by Poly(I:C) injection. Treatment with IFN-c in vitro triggered much higher activation of downstream signals (pSTAT1-IRF-1) in hepatocytes of HBs-B6 mice. Depletion of Kupffer cells and neutralization of endogenous IL-12 did not affect Poly(I:C)-induced over-sensitive liver injury in HBs-B6 mice.Conclusions: NK cells played a critical role in an IFN-c dependent, Kupffer cell-and IL-12-independent manner in oversensitive liver injury triggered by Poly(I:C) in murine chronic HBsAg carriers. Ó

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“…70 IFN-␥ production by these cells not only has antiviral effects but also mediates the intrahepatic recruitment of inflammatory cells. 71,72 Direct evidence of the activation state of NK and NK-T cells during the initial phase of HCV infection is lacking. Nevertheless, the absence of signs of liver inflammation in the first 4 to 6 weeks after HCV infection 10,38,41,44,63 suggests that the contribution of NK and/or NK-T cells in this early phase may be minimal.…”

Section: The Innate Immune Response In Hcv and Hbv Infectionsmentioning

confidence: 99%

Kinetics of the Immune Response During Hbv and Hcv Infection

2003

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The innate immune system has a role not only in protecting the host during the initial period of virus infection, but also in shaping the nature of the adaptive immune response. In this review, we follow the kinetics of the virologic and immunologic events occurring from the time of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We primarily discuss how the early events after infection might influence the development of the adaptive immune response in these 2 important viral infections and how new strategies for more efficient preventive and therapeutic vaccines can be derived from this knowledge. (HEPATOLOGY 2003; 38:4-13.)H epatitis B (HBV) and hepatitis C (HCV) viruses are the 2 major causes of chronic liver inflammation worldwide. 1,2 Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections share also some important features of the adaptive immune response. Multispecific antiviral CD4 and CD8 responses with a T-helper type 1 profile of cytokine production are detectable in the blood of subjects with a self-limited infection. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] These responses are stronger than those found in patients with chronic infection. [17][18][19][20][21] Based on these observations, it has been proposed that the ability to mount an efficient cellular immune response is the main mechanism responsible for HBV and HCV control, whereas a defect in this response leads to chronicity. 2,22 However, the lack of suitable animal models to study the pathogenesis of HBV and HCV infections has so far hampered a definitive demonstration that associations between different infection outcomes and different vigor and breadth of T-cell responses have a causative effect. A recent report in HCV-infected chimpanzees, in which a clear association between T-cell response and virus clearance was not found, 23 added a further note of caution. Even so, it is difficult to argue against the importance of the cellular immune response in HBV and HCV control. In chimpanzees infected with HCV, expansion of a multispecific and sustained HCV-specific CD8 ϩ T-cell-mediated response was observed in 2 of 2 animals that cleared the virus, but not in the 4 animals that developed a chronic infection. 24 These results have been confirmed by recent reports showing that expansion of interferon ␥ (IFN-␥) ϩ , CD8 ϩ , and CD4 ϩ T cells precedes viral clearance in patients studied during the incubation phase of acute HCV infection in man 10 and in HCV-infected chimpanzees. 25 Similar findings have been reported in animal models of HBV infection 26 and in patients studied during the incubation phase of HBV infection, 27 in whom reduced early expansion of virusspecific T cells was associated with virus persistence. Moreover, the importance of virus-specific CD8 ϩ T cells in HBV control has been confirmed further by CD8 ϩ T-cell deletion experiments performed in HBV-i...

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NK Cells Cause Liver Injury and Facilitate the Induction of T Cell-Mediated Immunity to a Viral Liver Infection

Cited by 130 publications

References 42 publications

Circulating natural killer and γδ T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus

Circulating natural killer and γδ T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Kinetics of the Immune Response During Hbv and Hcv Infection

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