Related Experiment Videos
Human cytomegalovirus strain-dependent changes in NK cell recognition of infected fibroblasts
C Cerboni1, M Mousavi-Jazi, A Linde
1Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden. cristina.cerboni@mtc.ki.se
Abstract:
NK cells play a key role in the control of CMV infection in mice, but the mechanism by which NK cells can recognize and kill CMV-infected cells is unclear. In this study, the modulation of NK cell susceptibility of human CMV (hCMV)-infected cells was examined. We used a human lung and a human foreskin fibroblast cell line infected with clinical isolates (4636, 13B, or 109B) or with laboratory strains (AD169, Towne). The results indicate that all three hCMV clinical isolates confer a strong NK resistance, whereas only marginal or variable effects in the NK recognition were found when the laboratory strains were used. The same results were obtained regardless of the conditions of infection, effector cell activation status, cell culture conditions, and/or donor-target cell combinations. The NK cell inhibition did not correlate with HLA class I expression levels on the surface of the target cell and was independent of the leukocyte Ig-like receptor-1, as evaluated in Ab blocking experiments. No relevant changes were detected in the adhesion molecules ICAM-I and LFA-3 expressed on the cell surface of cells infected with hCMV clinical and laboratory strains. We conclude that hCMV possesses other mechanisms, related neither to target cell expression of HLA-I or adhesion molecules nor to NK cell expression of leukocyte Ig-like receptor-1, that confer resistance to NK cell recognition. Such mechanisms may be lost during in vitro passage of the virus. These results emphasize the differences between clinical hCMV isolates compared with laboratory strains.
Insights
Human cytomegalovirus (hCMV) clinical isolates strongly resist NK cell killing, unlike lab strains. This resistance is independent of HLA-I and other known mechanisms, suggesting novel evasion strategies.
Area of Science:
- Immunology
- Virology
Background:
- Natural killer (NK) cells are crucial for controlling cytomegalovirus (CMV) infections.
- The precise mechanisms by which NK cells recognize and eliminate CMV-infected cells remain incompletely understood.
Purpose of the Study:
- To investigate how human cytomegalovirus (hCMV) infection alters the susceptibility of host cells to NK cell-mediated lysis.
- To compare the NK cell resistance conferred by clinical hCMV isolates versus laboratory strains.
Main Methods:
- Human lung and foreskin fibroblast cell lines were infected with various clinical isolates (4636, 13B, 109B) and laboratory strains (AD169, Towne) of hCMV.
- NK cell susceptibility was assessed under diverse experimental conditions, including varying infection parameters, effector cell activation, culture conditions, and donor-target cell pairings.
- Expression levels of HLA class I, ICAM-1, and LFA-3 on infected cells were analyzed.
- Antibody blocking experiments were performed to evaluate the role of leukocyte Ig-like receptor-1 (LIR-1).
Main Results:
- All tested hCMV clinical isolates induced significant resistance to NK cell-mediated killing.
- Laboratory strains (AD169, Towne) showed only marginal or variable effects on NK cell recognition.
- This NK resistance was consistently observed across different experimental conditions and cell combinations.
- Resistance did not correlate with changes in HLA class I, ICAM-1, or LFA-3 expression.
- The mechanism of resistance was independent of LIR-1 engagement.
Conclusions:
- hCMV clinical isolates possess potent mechanisms to evade NK cell detection and killing.
- These mechanisms are distinct from alterations in HLA class I or adhesion molecule expression and do not involve LIR-1.
- The observed differences suggest that in vitro passage may lead to the loss of critical viral evasion strategies present in clinical isolates.