Effect of a retroviral immunodeficiency syndrome on resistance to MCMV: a role for natural killer cells (original) (raw)
Related papers
Journal of Experimental Medicine, 2001
Antiviral roles of natural killer (NK) cell subsets were examined in C57BL/6 mice infected with murine cytomegalovirus (MCMV) and other viruses, including lymphocytic choriomeningitis virus (LCMV), vaccinia virus (VV), and mouse hepatitis virus (MHV). Each virus vigorously induced an NK cell infiltrate into the peritoneal cavity and liver, causing some redistributions of NK cell subsets defined by monoclonal antibody (mAb) directed against Ly49A, C/I, D, and G2. Striking results were seen with a mAb (1F8) reactive with the positively signaling molecule Ly49H, present in MCMV-resistant C57BL/6 mice. mAb 1F8 also stains Ly49 C and I, but exclusion of those reactivities with mAb 5E6, which recognizes Ly49 C and I, indicated that Ly49H+ cells infiltrated the peritoneal cavity and liver and were particularly effective at synthesizing interferon γ. Depletion of 1F8+ but not 5E6+ cells in vivo by mAb injections enhanced MCMV titers by 20-1,000-fold in the spleen and approximately fivefold ...
Modulation of natural killer cells by human cytomegalovirus
Journal of Clinical Virology, 2008
Human cytomegalovirus (HCMV) causes lifelong, persistent infections and its survival is under intense, continuous selective pressure from the immune system. A key aspect of HCMV's capacity for survival lies in immune avoidance. In this context, cells undergoing productive infection exhibit remarkable resistance to natural killer (NK) cell-mediated cytolysis in vitro. To date, six genes encoding proteins (UL16, UL18, UL40, UL83, UL141 and UL142) and one encoding a microRNA (miR-UL112) have been identified as capable of suppressing NK cell recognition. Even though HCMV infection efficiently activates expression of ligands for the NK cell activating receptor NKG2D, at least three functions (UL16, UL142 and miR-UL112) act in concert to suppress presentation of these ligands on the cell surface. Although HCMV downregulates expression of endogenous MHC-I, it encodes an MHC-I homologue (UL18) and also upregulates the expression of cellular HLA-E through the action of UL40. The disruption of normal intercellular connections exposes ligands for NK cell activating receptors on the cell surface, notably CD155. HCMV overcomes this vulnerability by encoding a function (UL141) that acts post-translationally to suppress cell surface expression of CD155. The mechanisms by which HCMV systematically evades (or, more properly, modulates) NK cell recognition constitutes an area of growing understanding that is enhancing our appreciation of the basic mechanisms of NK cell function in humans.
In this study, we investigated the eect of depletion of CD8 + T cells on the activity of natural killer (NK) cells at an early phase of murine cytomegalovirus (MCMV) infection. For CD8 + T cell depletion, mice were intraperitoneally treated with anti-CD8 mAb, puri®ed from 2.43 hybridoma, for 2 consecutive days before or after infection. Three days after infection, we found that an acute depletion of CD8 + T cells before infection caused a signi®cant decrease in the viral load in liver and spleen. This eect coincided with an increase in numbers of CD3 À NK1.1 + cells in spleen and their expression of the early activation molecule CD69. Although cytolytic activity of NK cells increased on day 3 of infection in CD8-depleted mice, the level of IFN-g decreased in serum and supernatant of cultured spleen cells. In contrast to the eect of acute depletion of CD8 + T cells before infection, the depletion after infection had no eect on the viral load or number and cytolytic function of NK cells. Lack of eects of CD8 + T cell depletion on the viral load and NK cytolytic activity is also observed in CD8 + knockout mice. In conclusion, the results suggest that an acute depletion of CD8 + T cells before MCMV infection eectively upregulated the antiviral activity of NK cells. This eect appears to be mediated through an increase in numbers, activation and cytolytic activity of NK cells. 7
Experimental …, 2007
Objective. Infection of immunocompromised patients with cytomegalovirus (CMV), such as that occurring in patients undergoing hematopoietic stem cell transplantation, is a serious clinical problem. CMV infection has been reported to suppress hematopoiesis. In immunocompetent hosts CMV is controlled initially by the innate immune system, with CD1d molecules and natural killer T (NKT) cells playing a role in the antiviral immune response in several model systems. We hypothesized that CD1d and NKT cells are involved in protection of the hematopoietic modulating effects of CMV, and that adoptive transfer of NKT cells would protect against these infection-induced effects. Methods. To address our hypothesis, we used a murine CMV (MCMV) infection model in CD1d L/L , Ja18 L/L , and wild-type (WT) control mice of two different genetic strains each. Results. Infection with MCMV was associated with significant suppression of absolute numbers and cell cycling status of myeloid progenitor cells (CFU-GM, BFU-E, CFU-GEMM) in the marrow and spleen, especially in CD1d L/L (lack both CD1d and NKT cells), and Ja18 L/L (express CD1d but lack NKT cells) mice. Adoptive transfer of NKT cells into WT and Ja18 L/L mice shortly before infection with MCMV counteracted myelosuppression. Conclusions. The results implicate NKT cells, and also likely CD1d, in protection of progenitor cells from MCMV-induced suppression and suggest that NKT cells may be of value in an adoptive transfer setting to treat CMV-induced perturbations of hematopoiesis in immunocompromised individuals. However, further studies are required to better understand the full consequences of adoptive transfer in these settings. Ó
Journal of Virology, 2014
ABSTRACTHuman cytomegalovirus (HCMV) transmission within the host is important for the pathogenesis of HCMV diseases. Natural killer (NK) cells are well known to provide a first line of host defense against virus infections. However, the role of NK cells in the control of HCMV transmission is still unknown. Here, we provide the first experimental evidence that NK cells can efficiently control HCMV transmission in different cell types. NK cells engage different mechanisms to control the HCMV transmission both via soluble factors and by cell contact. NK cell-produced interferon gamma (IFN-γ) suppresses HCMV production and induces resistance of bystander cells to HCMV infection. The UL16 viral gene contributes to an immune evasion from the NK cell-mediated control of HCMV transmission. Furthermore, the efficacy of the antibody-dependent NK cell-mediated control of HCMV transmission is dependent on a CD16-158V/F polymorphism. Our findings indicate that NK cells may have a clinical relev...
Nature Genetics, 2005
Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F 2 progeny from MCMV-resistant MA/My (H2 k ) and MCMV-susceptible BALB/c (H2 d ) and BALB.K (H2 k ) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 k haplotype. This binding was blocked using antibodies to H-2D k but not antibodies to H-2K k . These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D k on MCMV-infected cells.
Immunology, 1997
We describe here the activation of natural killer (NK) cells in the bone marrows and spleens of mice infected with murine cytomegalovirus (MCMV). NK activity at these sites peaked at day 2 to 3 post-infection (p.i.) and declined between days 6 and 10 p.i. in BALB/c and C57BL/6 mice. In BALB/c mice, the increases in NK activity coincided with depletion of colony-forming units of the granulocyte-monocyte lineage (CFU-GM) from the marrow. CFU-GM depletion in MCMV-infected C57BL/6 mice was less severe, despite the presence of activated NK cells in the marrow. Treatment of BALB/c mice with anti-asialo GM1 prior to MCMV infection resulted in less severe CFU-GM depletion at day 2 p.i. than infection with MCMV alone. When homozygous C57BL/6 or CBA/CaH bg/bg mice were infected with MCMV, depletion of marrow CFU-GM was more severe than in their heterozygous littermates. Finally, we observed some inhibition of colony formation when marrow cells from MCMV-infected and uninfected BALB/c donors were mixed and incubated prior to the CFU-GM assay. These results suggest that activated NK cells may contribute to depletion of haemopoietic cells soon after MCMV infection of BALB/c mice, but may limit the loss of these cells in C57BL/6 and CBA/CaH mice.