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

• Type of Material: Article
• Authors: M. Zeeshan Chaudhry, Helmholtz Centre for Infection Research; Rosaely Casalegno-Garduno, Helmholtz Centre for Infection Research; Katarzyna M. Sitnik, Helmholtz Centre for Infection Research; Bahram Kasmapour, Helmholtz Centre for Infection Research; Ann-Kathrin Pulm, Helmholtz Centre for Infection Research; Ilija Brizic, University of Rijeka; Britta Eiz-Vesper, Hannover Medical School; Andreas Moosmann, Helmholtz Zentrum Munchen; Stipan Jonjic, University of Rijeka; Edward Mocarski, Emory University; Luka Cicin-Sain, Helmholtz Centre for Infection Research
• Language: English
• Date: 2020-06-09
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: Published under the PNAS license
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1914667117
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 117
• Issue: 23
• Start Page: 12961
• End Page: 12968
• Grant/Funding Information: This work was supported by the Impulse and Networking Fund of the Helmholtz Association Grant VH-VI-424, DZIF through the research projects TTU 07.804 and TTU 07.817, and the DFG (Deutsche Forschungsgemeinschaft) Excellence Cluster RESIST, Research Area B2.1.
• Keywords: PERFORIN; Science & Technology; LYMPHOCYTE; Multidisciplinary Sciences; GENE-EXPRESSION; immune evasion; CD8 T cells; Science & Technology - Other Topics; CLASS-I COMPLEXES; ANTIGEN PRESENTATION; GRANZYME-B; IMMUNE EVASION; VIRUS; apoptosis inhibition; cytomegalovirus; INTERFERENCE; apoptosis; ACTIVATION
• Research Categories: Health Sciences, Immunology; Biology, Cell; Biology, Genetics; Biology, Virology

Abstract

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.