Antiviral CD8+ T cell effector activities in situ are regulated by target cell type

Abstract

In the lungs of mice infected with influenza, the activity of cytotoxic T lymphocytes is modulated by the type of target cell encountered.

Alveolar epithelial cells orchestrate DC function in murine viral pneumonia

“…Initially considered to function solely as a physical barrier providing gas exchange, the alveolar epithelium is now increasingly recognized as an important effector in fine-tuning antiviral immune responses at both onset and resolution of inflammation (4,5,34). Mononuclear phagocyte homeostasis, in particular, is controlled by such tissue-specific microenvironmental factors that either maintain a threshold for responsiveness to avoid continuous or excess inflammation (35) or establish immune competence before activation or after contact with antigen (36).…”

“…Histopathologic and clinical features of IV-induced lung injury in humans resemble those of other forms of adult respiratory distress syndrome (ARDS), characterized by apoptotic alveolar epithelial damage, loss of alveolar barrier function, and severe hypoxemia (1)(2)(3). As soon as the infection spreads from the upper to the lower respiratory tract, alveolar epithelial cells (AECs) become primary targets for productive IV replication (3)(4)(5). At the same time, AECs release innate immune mediators, which activate myeloid mononuclear phagocytes such as alveolar macrophages or DCs or recruit their precursors to the site of infection (6).…”

Influenza virus-induced lung injury: pathogenesis and implications for treatment

“…TNF-α, CCL3 and CCL5), but the role of these cytokines in viral clearance and/or the induction of lung injury is not clear [118]. Interestingly, a substantial body of evidence suggests that the cytolytic activity and cytokine function of effector T-cells are modified by factors present in the inflammatory milieu of the IAV-infected lung [119][120][121][122]. The complexity of these interactions is highlighted by the discovery that hHigh mobility group protein B1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule released from the infected epithelium, promotes the DC-dependent activation of IAV antigen-specific CD8 + T-effector cells via an interaction with RAGE (receptor for advanced glycation endproducts) [123].…”

Viral infection of the lung: Host response and sequelae

“…The excess production of proinflammatory cytokines can lead to enhanced inflammation and injury, resulting in immunopathology during pulmonary viral infection. 70 As with the initiation phase of the adaptive immune response (ie, the activation of naive antiviral T cells), available evidence suggests that the production of proinflammatory and regulatory cytokines by activated effector T cells in the infected lungs is dependent on costimulation (ie, recognition of costimulatory ligands, such as CD80, CD86, and CD70) displayed on the surface of myeloid lineage CD45 + inflammatory cells infiltrating the infected lungs recognized by costimulatory receptors on the antiviral effector T cells. For example, the in vivo blockade of CD80 and CD86 in experimental murine IAV infection markedly diminishes IFN-production by anti-IAV CTLs in the lung but has no effect on viral clearance from the lungs.…”

“…For example, the in vivo blockade of CD80 and CD86 in experimental murine IAV infection markedly diminishes IFN-production by anti-IAV CTLs in the lung but has no effect on viral clearance from the lungs. 70 In IAV-infected lungs some of the CD45 − lung parenchymal cell types, including type II alveolar epithelial cells, present viral antigens in the context of MHC-II molecules, which can be recognized and potentially trigger a cytotoxic response by effector CD4 + T cells. 71 However, at present, the contribution of CD4 + T-cell cytotoxicity to control viral replication and viral clearance in vivo in patients with IAV infection is not certain.…”