Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells.
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Zeeshan Chaudhry et al.pdf
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Authors
Chaudhry, M ZeeshanCasalegno-Garduno, Rosaely
Sitnik, Katarzyna M
Kasmapour, Bahram
Pulm, Ann-Kathrin
Brizic, Ilija
Eiz-Vesper, Britta
Moosmann, Andreas
Jonjic, Stipan
Mocarski, Edward S
Cicin-Sain, Luka

Issue Date
2020-05-22
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Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.Citation
Proc Natl Acad Sci U S A. 2020;117(23):12961-12968. doi:10.1073/pnas.1914667117.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
National Academy of SciencesPubMed ID
32444487Type
ArticleLanguage
enEISSN
1091-6490ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1914667117
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