Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner
| Autor: | Christian Walterskirchen, Florian Full, Julia Proff, Armin Ensser, Manfred Lehner, René Geyeregger, Wolfgang Holter, Charlotte U. Brey |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Microbiology (medical) T cell viruses Antigen presentation Streptamer Biology Microbiology 03 medical and health sciences Interleukin 21 herpesvirus medicine UL37x1 Cytotoxic T cell anti-apoptotic IL-2 receptor Antigen-presenting cell glycoprotein B cytomegalovirus Original Research immune evasion chimeric antigen receptor Natural killer T cell Virology 030104 developmental biology medicine.anatomical_structure UL36 |
| Zdroj: | Frontiers in Microbiology |
| ISSN: | 1664-302X |
| DOI: | 10.3389/fmicb.2016.00844 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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