Intraepithelial T-cell cytotoxicity, induced bronchus-associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza.

Stewart Sell, Ian Guest, K Kai McKinstry, Tara M Strutt, Jacob E Kohlmeier, Erik Brincks, Mike Tighe, Marcia A Blackman, David L Woodland, Richard W Dutton, Susan L Swain

Index: Viral Immunol. 27(10) , 484-96, (2014)

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Abstract

Immunopathologic examination of the lungs of mice with experimental influenza virus infection reveals three prominent findings. (i) There is rapidly developing perivascular (arterial) and peribronchial infiltration with T-cells and invasion of T-cells into the bronchiolar epithelium, separation of epithelial cells from each other and from the basement membrane, leading to defoliation of the bronchial epithelium. This reaction is analogous to a viral exanthema of the skin, such as measles and smallpox. This previously described but unappreciated reaction most likely is an effective way to eliminate virus-infected cells, but may contribute to acute toxicity and mortality. (ii) After this, there is formation of dense collections of lymphocytes adjacent to bronchi consisting mainly of B-cells, with a scattering of T-cells and macrophages. This is known as induced bronchial-associated lymphoid tissue (iBALT) and correlates with increased interleukin (IL)-17 in the lung. iBALT provides sites for a local immune reaction in the lung to both the original infection and related viral infections (heterologous immunity). (iii) Within the first 2-3 weeks, there is proliferation of type II pneumocytes and/or terminal bronchial epithelial cells extending from the terminal bronchioles into the adjacent alveoli, eventually leading to large zones of the lung filled with tumor-like epithelial cells with squamous metaplasia. The proliferation correlates with IL-17 and IL-22 expression, and the extent of this reaction appears to be determined by the availability of T-regulatory cells.