TNF-Induced Target Cell Killing by CTL Activated through Cross-Presentation

• Published in: Cell reports (Cambridge) 2012-09, Vol.2 (3), p.478-487
• Main Authors: Wohlleber, Dirk, Kashkar, Hamid, Gärtner, Katja, Frings, Marianne K., Odenthal, Margarete, Hegenbarth, Silke, Börner, Carolin, Arnold, Bernd, Hämmerling, Günter, Nieswandt, Bernd, van Rooijen, Nico, Limmer, Andreas, Cederbrant, Karin, Heikenwalder, Mathias, Pasparakis, Manolis, Protzer, Ulrike, Dienes, Hans-Peter, Kurts, Christian, Krönke, Martin, Knolle, Percy A.
• Format: Article
• Language: English
• Subjects: Adenoviridae - immunology; Adenoviridae Infections - immunology; Animals; Antigen Presentation - physiology; Costimulatory and Inhibitory T-Cell Receptors - immunology; Hepatocytes - immunology; Hepatocytes - virology; Immunity, Cellular - physiology; Immunologic Surveillance - physiology; Mice; Receptors, Tumor Necrosis Factor - immunology; Signal Transduction - immunology; T-Lymphocytes, Cytotoxic - immunology; Tumor Necrosis Factor-alpha - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.08.001

Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF. [Display omitted] ► Endothelial cell cross-presentation in infected tissue facilitates CTL immunity ► A CTL effector function acts independently of MHC recognition on target cells ► Viral infection sensitizes hepatocytes toward TNF-induced death Viral infection is controlled by effector CD8+ T cells (CTLs) recognizing their antigen on MHC I molecules on infected cells. Here, Knolle and colleagues report a previously unknown CTL effector function that is independent of direct recognition of infected cells. This noncanonical effector function is initiated by liver endothelial cell cross-presentation of antigens derived from infected hepatocytes to CTLs. TNF from activated CTLs selectively kills virus-infected hepatocytes. The noncanonical CTL effector function may prevent viral immune escape from CTL surveillance in infected tissues.