title: CD8 T cell-mediated lung damage in response to the extracellular pathogen pneumocystis is dependent on MHC class I expression by radiation-resistant lung cells.
abstract: Pneumocystis, a fungal, extracellular pathogen causes a life-threatening pneumonia in patients with severe immunodeficiencies. In the absence of CD4 T cells, Pneumocystis infection results in vigorous CD8 T cell influx into the alveolar and interstitial spaces of the lung. This response results in lung damage characterized by low pO2 and albumin leakage into the bronchoalveolar lavage fluid similar to other CD8 T cell-mediated interstitial lung diseases. How this extracellular pathogen elicits a CD8 T cell response is not clear, and it was the aim of our study to determine the Ag specificity of the recruited CD8 T cells and to determine whether MHC class I (MHC I) expression was necessary to initiate lung damage. Using an adoptive T cell-transfer model with either polyclonal wild-type CD8 T cells or transgenic influenza virus-specific CD8 T cells we found that CD8 T cell recruitment is Ag-specific and requires the continuous presence of the Pneumocystis pathogen. Bone marrow chimera experiments using Rag-1 and beta2-microglobulin-deficient mice as hosts demonstrated a requirement for MHC I expression on nonbone marrow-derived cells of the lung. This suggests either direct processing of Pneumocystis Ags by nonbone marrow-derived cells of the lung or the induction of lung damage triggered by a lung-specific autoantigen. Using perforin-, Fas-, and IFN-gamma-deficient animals, we showed that these molecules are not directly involved in the CD8-mediated lung damage. However, CD8 T cell-mediated lung damage is Ag-specific is induced by a MHC I-expressing nonbone marrow-derived cell in the lung and is dependent on the continued presence of live Pneumocystis.
authors.affiliation: Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA. nicolem@montana.edu
authors.forename: Nicole N
authors.initials: NN
authors.lastname: Meissner
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
authors.forename: Soo
authors.initials: S
authors.lastname: Han
authors.forename: Allen
authors.initials: A
authors.lastname: Harmsen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D008168:Lung / Q000473:pathology* / Q000528:radiation effects; D017563:Lung Diseases, Interstitial / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D011010:Pneumocystis / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity
chemical_list: D015395:Histocompatibility Antigens Class I