Hepatitis: Cruise MW

Lukens JR, Cruise MW, Lassen MG, Hahn YS. · Beirne Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA. · J Immunol. · Pubmed #18354211 links to  free full text

Abstract: The impaired function of CD8(+) T cells is characteristic of hepatitis C virus (HCV) persistent infection. HCV core protein has been reported to inhibit CD8(+) T cell responses. To determine the mechanism of the HCV core in suppressing Ag-specific CD8(+) T cell responses, we generated a transgenic mouse, core(+) mice, where the expression of core protein is directed to the liver using the albumin promoter. Using a recombinant adenovirus to deliver Ag, we demonstrated that core(+) mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. The effector function of LacZ-specific CD8(+) T cells was particularly impaired in the livers of core(+) mice, with suppression of IFN-gamma, TNF-alpha, and granzyme B production by CD8(+) T cells. In addition, the impaired CD8(+) T cell responses in core(+) mice were accompanied by the enhanced expression of the inhibitory receptor programmed death-1 (PD-1) by LacZ-specific CD8(+) T cells and its ligand B7-H1 on liver dendritic cells following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway (using a B7-H1 blocking antibody) in core(+) mice enhanced effector function of CD8(+) T cells and cleared Ad-LacZ-infection as compared with that in mice treated with control Ab. This suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence in the liver. This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection.

Cruise MW, Lukens JR, Nguyen AP, Lassen MG, Waggoner SN, Hahn YS. · Beirne Carter Center for Immunology Research, and Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA. · J Immunol. · Pubmed #16670334 links to  free full text

Abstract: Immune-mediated hepatic damage has been demonstrated in the pathogenesis of hepatitis C virus (HCV) and other hepatotrophic infections. Fas/Fas ligand (FasL) interaction plays a critical role in immune-mediated hepatic damage. To understand the molecular mechanism(s) of FasL-mediated liver inflammation, we examined the effect of CD4(+) T cells expressing high levels of FasL on the initiation of hepatic damage through analysis of chemokine and chemokine receptor expression in HCV core x TCR (DO11.10) double-transgenic mice. In vivo antigenic stimulation triggers a marked influx of core-expressing Ag-specific CD4(+) T cells into the liver of the immunized core(+) TCR mice but not their core(-) TCR littermates. Strikingly, the inflammatory process in the liver of core(+) TCR mice was accompanied by a dramatic increase in IFN-inducible protein 10 and monokine induced by IFN-gamma production. The intrahepatic lymphocytes were primarily CXCR3-positive and anti-CXCR3 Ab treatment abrogates migration of CXCR3(+) lymphocytes into the liver and hepatic damage. Importantly, the blockade of Fas/FasL interaction reduces the expression of IFN-inducible protein 10 and monokine induced by IFN-gamma and cellular infiltration into the liver. These findings suggest that activated CD4(+) T cells with elevated FasL expression are involved in promoting liver inflammation and hepatic damage through the induction of chemokines.

Waggoner SN, Cruise MW, Kassel R, Hahn YS. · Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville 22908, USA. · J Immunol. · Pubmed #16177118 links to  free full text

Abstract: gC1qR, a complement receptor for C1q, plays a pivotal role in the regulation of inflammatory and antiviral T cell responses. Several pathogens, including hepatitis C virus, exploit gC1qR-dependent regulatory pathways to manipulate host immunity. However, the molecular mechanism(s) of gC1qR signaling involved in regulating inflammatory responses remains unknown. We report the selective inhibition of TLR4-induced IL-12 production after cross-linking of gC1qR on the surface of macrophages and dendritic cells. Suppression of IL-12 did not result from increased IL-10 or TGF-beta, but was dependent on PI3K activation. Activation of PI3K and subsequent phosphorylation of Akt define an intracellular pathway mediating gC1qR signaling and cross-talk with TLR4 signaling. This is the first report to identify signaling pathways used by gC1qR-mediated immune suppression, and it establishes a means of complement-mediated immune suppression to inhibit Th1 immunity crucial for clearing pathogenic infection.

Cruise MW, Melief HM, Lukens J, Soguero C, Hahn YS. · Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA. · J Leukoc Biol. · Pubmed #15894587 links to  free full text

Abstract: Hepatitis C virus (HCV) infection is associated with a high rate of viral persistence and the development of chronic liver disease. The expression of HCV core protein in T cells has previously been reported to alter T cell activation and has been linked to the development of liver inflammation. However, the molecular and cellular basis for the role of HCV core-expressing T cells in liver inflammation is not understood. Here, using double-transgenic mice of CD2/HCV-core transgenic mice and ovalbumin (OVA)-specific T cell receptor transgenic mice, we demonstrated that in vivo antigenic stimulation (OVA peptide administration) triggers a marked influx of core-expressing, antigen-specific, transgenic CD4+ T cells into the liver of these mice. Phenotypic analysis of the liver-infiltrating T cells revealed high expression levels of CD44 and Fas ligand (FasL). Adoptive transfer of liver-infiltrating, core-expressing CD4+ T cells into severe combined immunodeficiency mice directly demonstrated the capacity of these activated T cells to induce liver inflammation. It is important that anti-FasL antibody treatment of the mice at the time of cell transfer abrogated the liver inflammation induced by core-expressing CD4+ T cells. These findings suggest that activated T lymphocytes expressing elevated levels of FasL may be involved in the bystander killing of hepatocyte, as well as the induction of chronic liver inflammation, by promoting recruitment of proinflammatory cells to the liver.

Yao ZQ, Waggoner SN, Cruise MW, Hall C, Xie X, Oldach DW, Hahn YS. · Beirne Carter Center for Immunology Research, Department of Microbiology and Pathology, University of Virginia, Charlottesville, Virginia 22908, USA. · J Virol. · Pubmed #16873288 links to  free full text

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Yao ZQ, Waggoner SN, Cruise MW, Hall C, Xie X, Oldach DW, Hahn YS. · Beirne Carter Center for Immunology Research, Department of Microbiology and Pathology, University of Virginia, Charlottesville, VA 22908, USA. · J Virol. · Pubmed #16306613 links to  free full text

Abstract: T cells play an important role in the control of hepatitis C virus (HCV) infection. We have previously demonstrated that the HCV core inhibits T-cell responses through interaction with gC1qR. We show here that core proteins from chronic and resolved HCV patients differ in sequence, gC1qR-binding ability, and T-cell inhibition. Specifically, chronic core isolates bind to gC1qR more efficiently and inhibit T-cell proliferation as well as gamma interferon (IFN-gamma) production more profoundly than resolved core isolates. This inhibition is mediated by the disruption of STAT phosphorylation through the induction of SOCS molecules. Silencing either SOCS1 or SOCS3 by small interfering RNA dramatically augments the production of IFN-gamma in T cells, thereby abrogating the inhibitory effect of core. Additionally, the ability of core proteins from patients with chronic infections to induce SOCS proteins and suppress STAT activation greatly exceeds that of core proteins from patients with resolved infections. These results suggest that the HCV core/gC1qR-induced T-cell dysfunction involves the induction of SOCS, a powerful inhibitor of cytokine signaling, which represents a novel mechanism by which a virus usurps the host machinery for persistence.