Infection with respiratory viruses such as with influenza, particularly the highly pathogenic strains, results in considerable pulmonary immunopathology, a large component of which results from the host T cell responses. This lung injury is an important determinant of clinical outcome in such infections. We have developed a model to distinguish the lung injury that is specifically due to CD8+ T cell recognition of viral antigen on lung epithelium and T cell effector activities triggered thereby, from that which results from the cyopathic effects of the virus itself. In this proposal we aim to extend the characterization of CD8+ T cell mediated injury to dissect the complex immunopathologic processes associated with T cell responses in the presence of influenza pneumonia. We have found a significant difference between highly injurious and minimally injurious T cell populations in their threshold for processing transmembrane TNF to its soluble form. As a proof of principle, we have developed CD8+ T cells which exclusively express a non-cleavable transmembrane form of TNF, and have observed a marked reduction in injury potential. The pathology triggered by these T cells is remarkable for significant interstitial/septal cellular infiltration without significant infiltration of the alveolar space and without evidence of edema or hemorrhage. Furthermore, while WT T cell-mediated injury is characterized by transient accumulation of PMNs in the first 12-24 hours after T cell engagement, followed by dramatic accumulation of macrophages, this PMN influx was not evident after transfer of the mutant T cells. Gas exchange was only mildly impaired in recipients of the mutant T cells. We hypothesize that the threshold for processing of transmembrane TNF determines the severity of the injury after CD8+ T cell recognition. We further hypothesize that the mechanism of enhanced injury mediated by soluble TNF produced in an antigen-specific fashion is the induction of neutrophil chemoattractant expression by alveolar epithelial cells, in response to T cell recognition, which leads to early and transient neutrophil recruitment to the alveolar space. This appears to mediated by TNF-R2 (p75) leading to exuberant ERK activation and Egr-1 expression. We will study WT and mutant CD8+ T cell populations, and a variety of transgenic mice expressing mutant TNF receptors in order to understand how CD8+ TNF processing to the soluble species triggers severe lung injury, and the mechanisms of regulation.
|DeBerge, Matthew P; Ely, Kenneth H; Cheng, Guang-Shing et al. (2013) ADAM17-mediated processing of TNF-? expressed by antiviral effector CD8+ T cells is required for severe T-cell-mediated lung injury. PLoS One 8:e79340|
|Gifford, A H; Matsuoka, M; Ghoda, L Y et al. (2012) Chronic inflammation and lung fibrosis: pleotropic syndromes but limited distinct phenotypes. Mucosal Immunol 5:480-4|
|Srikiatkhachorn, Anon; Chintapalli, Jyothi; Liu, Jun et al. (2010) Interference with intraepithelial TNF-ýý signaling inhibits CD8(+) T-cell-mediated lung injury in influenza infection. Viral Immunol 23:639-45|
|Ramana, Chilakamarti V; Cheng, Guang-Shing; Kumar, Aseem et al. (2009) Role of alveolar epithelial early growth response-1 (Egr-1) in CD8+ T cell-mediated lung injury. Mol Immunol 47:623-31|
|Zhou, Jing; Matsuoka, Mitsuo; Cantor, Harvey et al. (2008) Cutting edge: engagement of NKG2A on CD8+ effector T cells limits immunopathology in influenza pneumonia. J Immunol 180:25-9|