title: CD4+ T cells and IFN-γ are required for the development of Pneumocystis-associated pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is a disease of diverse etiology. Although primary PH can develop in the absence of prior disease, PH more commonly develops in conjunction with other pulmonary pathologies. We previously reported a mouse model in which PH occurs as a sequela of Pneumocystis infection in the context of transient CD4 depletion. Here, we report that instead of the expected Th2 pathways, the Th1 cytokine IFN-γ is essential for the development of PH, as wild-type mice developed PH but IFN-γ knockout mice did not. Because gene expression analysis showed few strain differences that were not immune-function related, we focused on those responses as potential pathologic mechanisms. In addition to dependence on IFN-γ, we found that when CD4 cells were continuously depleted, but infection was limited by antibiotic treatment, PH did not occur, confirming that CD4 T cells are required for PH development. Also, although CD8 T-cells are implicated in the pathology of Pneumocystis pneumonia, they did not have a role in the onset of PH. Finally, we found differences in immune cell phenotypes that correlated with PH, including elevated CD204 expression in lung CD11c(+) cells, but their role remains unclear. Overall, we demonstrate that a transient, localized, immune response requiring IFN-γ and CD4-T cells can disrupt pulmonary vascular function and promote lingering PH.
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana. Electronic address: uvsss@montana.edu.
authors.forename: Steve D
authors.initials: SD
authors.lastname: Swain
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana.
authors.forename: Dan W
authors.initials: DW
authors.lastname: Siemsen
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Pullen
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana.
authors.forename: Soo
authors.initials: S
authors.lastname: Han
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005355:Fibrosis; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000150:complications / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D007109:Immunity / Q000235:genetics; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D011010:Pneumocystis / Q000502:physiology*; D011020:Pneumonia, Pneumocystis / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C495140:Msr1 protein, mouse; D050800:STAT6 Transcription Factor; D051117:Scavenger Receptors, Class A; C494100:Stat6 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma