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Zeeshan Chaudhry, M.* ; Casalegno-Garduno, R.* ; Sitnik, K.M.* ; Kasmapour, B.* ; Pulm, A.K.* ; Brizic, I.* ; Eiz-Vesper, B.* ; Moosmann, A. ; Jonjic, S.* ; Mocarski, E.S.* ; Cicin-Sain, L.*

Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells.

Proc. Natl. Acad. Sci. U.S.A. 117, 12961-12968 (2020)
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Viral immune evasion is currently understood to focus on deflect-ing 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) pre-vents 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 immunoeva-sins 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 mech-anism through which vICA acts, demonstrating the central contribu-tion of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Immune Evasion ; Cytomegalovirus ; Apoptosis Inhibition ; Apoptosis ; Cd8 T Cells; Class-i Complexes; Antigen Presentation; Immune Evasion; Granzyme-b; Gene-expression; Lymphocyte; Virus; Perforin; Interference; Activation
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 117, Issue: 23, Pages: 12961-12968 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-501500-001
DOI 10.1073/pnas.1914667117
WOS ID WOS:000545946100005
Scopus ID 85086239444
PubMed ID 32444487
Erfassungsdatum 2020-06-19
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