Immune responses and cytokine induction in the development of severe hepatitis during acute infections with murine cytomegalovirus (original) (raw)
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Clinical & Experimental Immunology, 2008
Mice susceptible and resistant to murine cytomegalovirus (MCMV) were infected with this virus and livers were harvested after 2-231 days. Cryostat sections were stained to visualize cells bearing CD4, CD8 or Mac-I antigens. Mac-1+ cells were prevalent in inflammatory foci after 2 days. These cells persisted in susceptible BALB/c and A/J mice, but disappeared from livers of resistant C57B1/ 6 and CBA/CaH mice by day 28. T cell inflammation peaked on days 7-1 1. This declined by day 56 in C57B1/6 and CBA/CaH mice, but persisted in BALB/c and A/J mice for at least 231 days. Persistent CD8+ cells were dispersed throughout the parenchyma. More CD8+ cells were observed 7-14 days after infection in the livers of bg/bg (natural killer (NK) cell-deficient) C57B1/6 and CBA mice, and in C57B1/6 mice depleted of NK1. 1 cells by MoAb. Thus, mice of strains susceptible to MCMV exhibit hepatitis characterized by persistence of dispersed CD8+ cells. This phenomenon may be limited by NK cells in resistant strains.
Antiviral T Cell Response Triggers Cytomegalovirus Hepatitis in Mice
Journal of Virology, 2012
One common sign of human cytomegalovirus infection is altered liver function. Murine cytomegalovirus strain v70 induces a rapid and severe hepatitis in immunocompetent mice that requires the presence of T cells in order to develop. v70 exhibits approximately 10-fold-greater virulence than the commonly used strain K181, resulting in a more severe, sustained, and lethal hepatitis but not dramatically higher viral replication levels. Hepatitis and death are markedly delayed in immunodeficient SCID compared to immunocompetent BALB/c mice. Transfer of BALB/c splenocytes to SCID mice conferred rapid disease following infection, and depletion of either CD4 or CD8 T cells in BALB/c mice reduced virus-induced hepatitis. The frequency of CD8 T cells producing gamma interferon and tumor necrosis factor in response to viral antigen was higher in settings where more severe disease occurred. Thus, virus-specific effector CD8 T cells appear to contribute to lethal virus-induced hepatitis, contrasting their protective role during sublethal infection. This study reveals how protection and disease during cytomegalovirus infection depend on viral strain and dose, as well as the quality of the T cell response.
Immunology, 1997
The roles of the inflammatory cytokines tumour necrosis factor-ac (TNF-a), interleukin-l (IL-1) and IL-12, in murine cytomegalovirus (MCMV) disease were investigated in susceptible BALB/c and resistant C57BL/6 mice. MCMV infection induced IL-1 and TNF-ca production by peritoneal cells from BALB/c mice, as demonstrated previously in C57BL/6 mice. Overt ill-health and viral replication in the spleens of BALB/c mice were increased by in vivo treatment with soluble TNFa receptors to inhibit the activity of this cytokine, whilst antibodies to IL-12 had a similar but more restricted effect. C57BL/6 mice were not affected by either treatment, suggesting TNF-a and IL-12 are not critical for natural killer cell-mediated restriction of viral replication in the spleen. Soluble TNF-a receptors and antibodies to IL-12 also enhanced MCMV titres and numbers of viral antigen-positive cells in the livers of BALB/c mice and TNF-ca receptors have similar effects in C57BL/6 livers. In contrast, IL-1 receptors improved the health of MCMV-infected BALB/c mice and reduced viral replication and hepatitis at some time-points. Mechanisms which may underlie these changes are discussed.
Immunology, 2000
Cytomegalovirus (CMV) causes severe opportunistic infection in immunocompromised hosts. The importance of conventional ab T cells in protection against CMV infection has been well documented. However, the role of the second T-cell population (which express the cd T-cell receptor) in CMV infection is not known. In the present study, we analysed the function and protective role of cd T cells in a murine cytomegalovirus (MCMV) infection model. After intraperitoneal infection with MCMV, the number of cd T cells increased in the liver and peritoneal cavity from day 3, and reached a peak on day 5. The cd T cells showed an activated T-cell phenotype and predominantly expressed Vc1, which is known to be expressed by heat-shock protein 65 (hsp 65)-speci®c cd T cells. Analysis of cytokine expression demonstrated that the MCMV-induced cd T cells expressed interferon-c (IFN-c) and tumour necrosis factor-a (TNF-a) but not interleukin-4 (IL-4), implying their participation in the cell-mediated immune response against MCMV. Depletion of cd T cells by anti-T-cell receptor (TCR) cd monoclonal antibody (mAb) treatment resulted in signi®cant increase of virus titre and decrease of IFN-c in the liver on day 3 after MCMV infection, which further supports the importance of cd T cells in early protection against infection. Finally, the MCMV-induced cd T cells produced IFN-c in vitro in response to hsp 65. Our results suggest that cd T cells participate in early protection against MCMV infection through recognition of hsp 65 and production of IFN-c.
Immunology, 2000
Cytomegalovirus (CMV) causes severe opportunistic infection in immunocompromised hosts. The importance of conventional ab T cells in protection against CMV infection has been well documented. However, the role of the second T-cell population (which express the cd T-cell receptor) in CMV infection is not known. In the present study, we analysed the function and protective role of cd T cells in a murine cytomegalovirus (MCMV) infection model. After intraperitoneal infection with MCMV, the number of cd T cells increased in the liver and peritoneal cavity from day 3, and reached a peak on day 5. The cd T cells showed an activated T-cell phenotype and predominantly expressed Vc1, which is known to be expressed by heat-shock protein 65 (hsp 65)-speci®c cd T cells. Analysis of cytokine expression demonstrated that the MCMV-induced cd T cells expressed interferon-c (IFN-c) and tumour necrosis factor-a (TNF-a) but not interleukin-4 (IL-4), implying their participation in the cell-mediated immune response against MCMV. Depletion of cd T cells by anti-T-cell receptor (TCR) cd monoclonal antibody (mAb) treatment resulted in signi®cant increase of virus titre and decrease of IFN-c in the liver on day 3 after MCMV infection, which further supports the importance of cd T cells in early protection against infection. Finally, the MCMV-induced cd T cells produced IFN-c in vitro in response to hsp 65. Our results suggest that cd T cells participate in early protection against MCMV infection through recognition of hsp 65 and production of IFN-c.
Participation of endogenous tumour necrosis factor in host resistance to cytomegalovirus infection
Journal of General Virology, 1993
Interferon gamma (IFNT) represents an essential cytokine involved in murine cytomegalovirus (MCMV) clearance from the salivary gland and the control of horizontal transmission. Because IFN 7 cannot be responsible for all cytokine effects during recovery from MCMV infection we have now tested the potential participation of tumour necrosis factor alpha (TNFct) in the antiviral defence. Neutralization of endogenous TNF~ abolished the antiviral activity of CD4 T cells in immunocompetent as well as in CD8 subset-deficient mice. These data suggest that the antiviral effect of the CD4 subset requires the presence of at least two cytokines, namely IFN7 and TNF~. Depletion of endogenous TNF~ in adoptive cell transfer recipients diminished the antiviral function of CD8 T lymphocytes suggesting that TNFct also participates in CD8 T cell effector functions. Furthermore, endogenous cytokines were found to be required for survival after infection with lethal doses of MCMV, whereas immunotherapy with recombinant TNF~ and IFN~ could not limit virus replication in vivo. The results suggest that, similar to IFNy, TNFct is an integral part of the protective mechanisms involved in cytomegalovirus clearance. 0001-17440001- © 1993
Characterization of CD4- CD8- CD3+ T-cell receptor-αβ+ T cells in murine cytomegalovirus infection
Immunology, 2000
In this study, we have investigated that after the intraperitoneal infection with murine cytomegalovirus (MCMV), the CD3 + CD4 ± CD8 ± (double negative; DN) T-cell receptor (TCR)ab + T cells increased in peritoneal cavity, liver and spleen in both resistant C57BL/6 and susceptible BALB/c mice. The total cellular population of these cells showed peak levels around day 5 after infection in all the three investigated organs and the following phenotypical and functional characteristics emerged. The peritoneal DN TCRab + T cells expressed highly skewed TCRVb8 on day 5 after infection compared with the uninfected mice, but those in spleen and liver showed moderate and low skewed TCRVb8, respectively. The percentages of NK1.1 + DN TCRab + T cells gradually decreased as did modulation of some of their activation markers consistent with an activated cell phenotype. The peritoneal DN TCRab + T cells on day 5 after infection expressed the genes of interferon-c (IFN-c), tumour necrosis factor-a, Eta-1 (early T-cell activation-1) and MCP-1 (monocyte chemoattractant protein 1) but lacked expression of interleukin-4 (IL-4). After in vitro stimulation with phorbol 12-myristate 13-acetate and calcium ionophore in the presence of Brefeldin A, higher frequencies of intracellular IFN-c + DN TCRab + T cells were detected in all three investigated organs of infected mice compared with those of uninfected mice. Stimulation of peritoneal DN TCRab + T cells with plate-bound anti-TCRb monoclonal antibodies showed proliferation and also produced IFN-c but not IL-4. These results suggest that DN TCRab + T cells were activated and may have an antiviral effect through producing IFN-c and some macrophageactivating factors during an early phase of MCMV infection.
International Journal of Experimental Pathology
We characterized liver-infiltrating leucocytes (LIL) from BALB/c and C57BL/6 mice 0-56 days after murine cytomegalovirus (MCMV) infection. Inflammation clears from C57BL/6 mice 4-5 weeks post infection (pi), but persists for several months in BALB/c mice. The LIL obtained were 60-80% Thy 1.2 þ by flow cytometry. The percentage of CD8 þ cells rose sharply in all mice 7 days pi, with little decrease in BALB/c mice by day 56. CD4 ¹ CD8 ¹ Thy1.2 þ /TCRab þ cells were more prevalent in LIL than lymph node cells (LNC) irrespective of MCMV infection, whilst infection increased the proportion of CD8 þ L-selectin ¹ LIL (but not LNC). LIL from both mouse strains demonstrated cytotoxic activity against YAC-1 cells, but only LIL from BALB/c mice proliferated spontaneously ex vivo 21 days pi, as measured by tritiated thymidine incorporation. BALB/c LIL produced IFNg and IgG 2a 7-21 days pi, whilst IL-10 secretion was similar in both strains. Thus, persistent hepatitis in BALB/c mice is associated with activation and proliferation of intrahepatic leucocytes with some bias towards a Th1 response.