Vγ1+γδ T cells play protective roles at an early phase of murine cytomegalovirus infection through production of interferon-γ (original) (raw)
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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.
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.
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.
Archives of Virology, 2000
Salivary gland-derived murine cytomegalovirus (SGV) infections of mice have been widely used as models of human cytomegalovirus infections and in the study of CMV biology. Still, many aspects of SGV pathogenesis are not clearly defined. Fatal and non-fatal SGV infections were investigated to characterize pathogenetic correlates of mortality and to assess the role of the immune response in disease progression. Suppression of immune responses was observed in both lethal and sublethal infections. Depletion of immune cell populations in spleen, however, correlated with severe CMV-induced hepatitis and mortality. In addition, T cell depletion studies indicated a requirement for this immune cell subset in control of liver damage and survival of infected mice. Examination of cytokine responses revealed a previously undescribed shock-like syndrome in lethally-infected mice characterized by high levels of tumor necrosis factor ␣ and interferon ␥. Furthermore, the sites of tumor necrosis factor ␣ gene induction did not strictly correlate with either viral load or the sites of tissue damage during infection. Taken together, these findings define the pathogenetic progression of disease as it relates to disease outcome and suggests that organ-specific differences in cytokine induction play a significant role in the late stages of acute lethal MCMV infections.
Blood, 2003
The correlates of protective immunity to disease-inducing viruses in humans remain to be elucidated. We determined the kinetics and characteristics of cytomegalovirus (CMV)-specific CD4 ؉ and CD8 ؉ T cells in the course of primary CMV infection in asymptomatic and symptomatic recipients of renal transplants. Specific CD8 ؉ cytotoxic T lymphocyte (CTL) and antibody responses developed regardless of clinical signs. CD45RA ؊ CD27 ؉ CCR7 ؊ CTLs, al-though classified as immature effector cells in HIV infection, were the predominant CD8 effector population in the acute phase of protective immune reactions to CMV and were functionally competent. Whereas in asymptomatic individuals the CMV-specific CD4 ؉ T-cell response preceded CMV-specific CD8 ؉ T-cell responses, in symptomatic individuals the CMV-specific effectormemory CD4 ؉ T-cell response was delayed and only detectable after antiviral therapy.
Blood, 2003
The correlates of protective immunity to disease-inducing viruses in humans remain to be elucidated. We determined the kinetics and characteristics of cytomegalovirus (CMV)-specific CD4 ؉ and CD8 ؉ T cells in the course of primary CMV infection in asymptomatic and symptomatic recipients of renal transplants. Specific CD8 ؉ cytotoxic T lymphocyte (CTL) and antibody responses developed regardless of clinical signs. CD45RA ؊ CD27 ؉ CCR7 ؊ CTLs, al-though classified as immature effector cells in HIV infection, were the predominant CD8 effector population in the acute phase of protective immune reactions to CMV and were functionally competent. Whereas in asymptomatic individuals the CMV-specific CD4 ؉ T-cell response preceded CMV-specific CD8 ؉ T-cell responses, in symptomatic individuals the CMV-specific effectormemory CD4 ؉ T-cell response was delayed and only detectable after antiviral therapy.
Innate Immunity to Viruses: Control of Vaccinia Virus Infection by γδ T Cells
The Journal of Immunology, 2001
The existence of γδ T cells has been known for over 15 years, but their significance in innate immunity to virus infections has not been determined. We show here that γδ T cells are well suited to provide a rapid response to virus infection and demonstrate their role in innate resistance to vaccinia virus (VV) infection in both normal C57BL/6 and β TCR knockout (KO) mice. VV-infected mice deficient in γδ T cells had significantly higher VV titers early postinfection (PI) and increased mortality when compared with control mice. There was a rapid and profound VV-induced increase in IFN-γ-producing γδ T cells in the peritoneal cavity and spleen of VV-infected mice beginning as early as day 2 PI. This rapid response occurred in the absence of priming, as there was constitutively a significant frequency of VV-specific γδ T cells in the spleen in uninfected β TCR KO mice, as demonstrated by limiting dilution assay. Also, like NK cells, another mediator of innate immunity to viruses, γδ T ...
Clinical and Vaccine Immunology, 2001
Antigen-specific CD8+ T cells with cytotoxic activity are often critical in immune responses to infectious pathogens. To determine whether gamma interferon (IFN-γ) expression is a surrogate marker for cytotoxic T lymphocytes (CTL), human cytomegalovirus-specific CTL responses were correlated with CD8+ T-cell IFN-γ expression determined by cytokine flow cytometry. A strong positive correlation was observed between specific lysis of peptide-pulsed targets in a 51Cr release assay and frequencies of peptide-activated CD8+ T cells expressing IFN-γ at 6 h (r 2 = 0.72) or 7 days (r 2 = 0.91). Enumeration of responding cells expressing perforin, another marker associated with CTL, did not improve this correlation. These results demonstrate that IFN-γ expression can be a functional surrogate for identification of CTL precursor cells.
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.