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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-RES-C (03))
Program Officer
Davidson, Wendy F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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