AUTHOR=de la Rua Nicholas M. , Samuelson Derrick R. , Charles Tysheena P. , Welsh David A. , Shellito Judd E. TITLE=CD4+ T-Cell-Independent Secondary Immune Responses to Pneumocystis Pneumonia JOURNAL=Frontiers in Immunology VOLUME=7 YEAR=2016 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00178 DOI=10.3389/fimmu.2016.00178 ISSN=1664-3224 ABSTRACT=

Pneumocystis pneumonia is a major cause of morbidity and mortality among immunocompromised patients, especially in the context of HIV/AIDS. In the murine model of Pneumocystis pneumonia, CD4⁺ T-cells are required for clearance of a primary infection of Pneumocystis, but not the memory recall response. We hypothesized that the memory recall response in the absence of CD4⁺ T-cells is mediated by a robust memory humoral response, CD8⁺ T-cells, and IgG-mediated phagocytosis by alveolar macrophages. To investigate the role of CD8⁺ T-cells and alveolar macrophages in the immune memory response to Pneumocystis, mice previously challenged with Pneumocystis were depleted of CD8⁺ T-cells or alveolar macrophages prior to re-infection. Mice depleted of CD4⁺ T-cells prior to secondary challenge cleared Pneumocystis infection within 48 h identical to immunocompetent mice during a secondary memory recall response. However, loss of CD8⁺ T-cells or macrophages prior to the memory recall response significantly impaired Pneumocystis clearance. Specifically, mice depleted of CD8⁺ T-cells or alveolar macrophages had significantly higher fungal burden in the lungs. Furthermore, loss of alveolar macrophages significantly skewed the lung CD8⁺ T-cell response toward a terminally differentiated effector memory population and increased the percentage of IFN-γ⁺ CD8⁺ T-cells. Finally, Pneumocystis-infected animals produced significantly more bone marrow plasma cells and Pneumocystis-specific IgG significantly increased macrophage-mediated killing of Pneumocystis in vitro. These data suggest that secondary immune memory responses to Pneumocystis are mediated, in part, by CD8⁺ T-cells, alveolar macrophages, and the production of Pneumocystis-specific IgG.