Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells.
Animals
Apoptosis
/ immunology
Caspase 8
/ genetics
Cell Line
Coculture Techniques
Cytomegalovirus
/ immunology
Cytomegalovirus Infections
/ immunology
Disease Models, Animal
Fibroblasts
Granzymes
/ metabolism
Histocompatibility Antigens Class I
/ immunology
Host Microbial Interactions
/ immunology
Humans
Immune Evasion
Mice
Mice, Knockout
Muromegalovirus
/ genetics
Mutagenesis
Perforin
/ genetics
Receptors, Death Domain
/ metabolism
Signal Transduction
/ immunology
T-Lymphocytes, Cytotoxic
/ immunology
Time-Lapse Imaging
Viral Proteins
/ genetics
CD8 T cells
apoptosis
apoptosis inhibition
cytomegalovirus
immune evasion
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
09 06 2020
09 06 2020
Historique:
pubmed:
24
5
2020
medline:
22
8
2020
entrez:
24
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32444487
pii: 1914667117
doi: 10.1073/pnas.1914667117
pmc: PMC7293702
doi:
Substances chimiques
Histocompatibility Antigens Class I
0
M36 protein, mouse cytomegalovirus
0
Receptors, Death Domain
0
UL36 protein, Human herpesvirus 1
0
Viral Proteins
0
perforin 1, mouse
0
Perforin
126465-35-8
Granzymes
EC 3.4.21.-
CASP8 protein, human
EC 3.4.22.-
Casp8 protein, mouse
EC 3.4.22.-
Caspase 8
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
12961-12968Subventions
Organisme : NIAID NIH HHS
ID : R01 AI020211
Pays : United States
Commentaires et corrections
Type : ErratumIn
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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