title: Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner.
abstract: In order to explore the potential of HLA-independent T cell therapy for human cytomegalovirus (HCMV) infections, we developed a chimeric antigen receptor (CAR) directed against the HCMV encoded glycoprotein B (gB), which is expressed at high levels on the surface of infected cells. T cells engineered with this anti-gB CAR recognized HCMV-infected cells and released cytokines and cytotoxic granules. Unexpectedly, and in contrast to analogous approaches for HIV, Hepatitis B or Hepatitis C virus, we found that HCMV-infected cells were resistant to killing by the CAR-modified T cells. In order to elucidate whether this phenomenon was restricted to the use of CARs, we extended our experiments to T cell receptor (TCR)-mediated recognition of infected cells. To this end we infected fibroblasts with HCMV-strains deficient in viral inhibitors of antigenic peptide presentation and targeted these HLA-class I expressing peptide-loaded infected cells with peptide-specific cytotoxic T cells (CTLs). Despite strong degranulation and cytokine production by the T cells, we again found significant inhibition of lysis of HCMV-infected cells. Impairment of cell lysis became detectable 1 day after HCMV infection and gradually increased during the following 3 days. We thus postulate that viral anti-apoptotic factors, known to inhibit suicide of infected host cells, have evolved additional functions to directly abrogate T cell cytotoxicity. In line with this hypothesis, CAR-T cell cytotoxicity was strongly inhibited in non-infected fibroblasts by expression of the HCMV-protein UL37x1, and even more so by additional expression of UL36. Our data extend the current knowledge on Betaherpesviral evasion from T cell immunity and show for the first time that, beyond impaired antigen presentation, infected cells are efficiently protected by direct blockade of cytotoxic effector functions through viral proteins.
authors.affiliation: Children's Cancer Research Institute, St. Anna KinderkrebsforschungVienna, Austria; Children's University Hospital, Universitätsklinikum ErlangenErlangen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Proff
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Walterskirchen
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung Vienna, Austria.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brey
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung Vienna, Austria.
authors.forename: Rene
authors.initials: R
authors.lastname: Geyeregger
authors.affiliation: Institute for Clinical and Molecular Virology, Universitätsklinikum ErlangenErlangen, Germany; Department of Microbiology, The University of ChicagoChicago, IL, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Full
authors.affiliation: Institute for Clinical and Molecular Virology, Universitätsklinikum Erlangen Erlangen, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Ensser
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung Vienna, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Lehner
authors.affiliation: Children's Cancer Research Institute, St. Anna KinderkrebsforschungVienna, Austria; Department of Pediatrics, St. Anna Kinderspital, Medical University of ViennaVienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Holter
keywords: UL36; UL37x1; anti-apoptotic; chimeric antigen receptor; cytomegalovirus; glycoprotein B; herpesvirus; immune evasion