Summary auto-generated
This study investigated whether MHC class I molecules serve as receptors for murine cytomegalovirus (MCMV) by comparing infection in β2-microglobulin-deficient mice (β2m−/−), which lack functional MHC class I complexes and CD8+ T cells, with wild-type controls. Contrary to previous in vitro findings suggesting MHC class I molecules are essential for MCMV entry, the researchers found no significant differences in virus titers or clearance kinetics between β2m−/− and heterozygous mice in infected organs. Embryonic fibroblasts from β2m−/− mice were equally permissive for MCMV infection as control cells. While β2m−/− mice showed increased susceptibility to virulent virus and reduced antibody responses, this correlated with CD8+ T cell deficiency rather than impaired viral entry. CD4+ T lymphocytes partially compensated for absent CD8+ cells during low-virulence infection. Salivary gland infection showed unique immune control mechanisms involving CD4+ T cells and natural killer cells, independent of MHC class I expression. The findings suggest MHC class I molecules are not the primary receptor for MCMV but play important roles in immune surveillance and CD8+ T cell-mediated viral control.
Key findings
- MHC class I-deficient β2m−/− mice showed similar MCMV spread and tissue clearance kinetics compared to wild-type mice, contradicting the hypothesis that MHC class I serves as the main viral receptor
- Embryonic fibroblasts from β2m−/− mice were equally permissive for productive MCMV infection as MHC class I-positive controls
- CD4+ T lymphocytes compensate for absent CD8+ T cells during chronic low-virulence infection, though this compensation fails against acute virulent virus challenge
- β2m−/− mice exhibited organ-specific differences in immune control, with salivary gland infection being controlled by CD4+ T cells and NK cells independent of MHC class I
- The impaired antibody response in β2m−/− mice did not significantly affect control of acute MCMV infection, suggesting CD8+ T cells are the critical immune mechanism
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Abstract
It has been claimed that MHC class I proteins serve as receptors for murine cytomegalovirus (MCMV) and that this interaction is the most important mechanism for virus entry in most cells. This claim is based on the observation that the MHC haplotype contributes to the susceptibility to cytomegalovirus (CMV) infection in vivo. Results from in vitro studies support the concept that stable expression of correctly folded MHC class I molecules contributes to infection, since the individual properties of MHC class I alleles, the availability of 2-microglobulin (2m) and also the degree of peptide charging of the MHC class I heavy chain 2m heterodimers determined the infection phenotype of cell lines. To assess the biological relevance of proper MHC class I expression we investigated CMV infection in 2m-deficient mice which fail to express ternary MHC class I complexes and lack peripheral CD8+ T lymphocytes. We found that organ virus titres and virus clearance kinetics were not altered in 2m mutant mice. In addition, there was no indication of diminished virus propagation in 2m-/- embryonic fibroblasts. 2m-/- mice suffered from the lack of CD8+ T lymphocytes that was partially compensated for by the function of CD4+ T lymphocytes. An organ-specific anti-virus function of natural killer (NK) cells was observed, independent from the 2m deletion. The immune control unique for salivary gland infection was maintained. From the data presented here, we confirm the role of MHC class I molecules in the immune surveillance of CMV infection but question the biological impact of correct MHC class I complexes for productive infection.
* Author for correspondence. Fax +49 6221 563953. e-mail Koszino@novsrvl.piol.uni-heidelberg.de