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.
Highlights
Pneumonia due to the opportunistic human fungal pathogen Pneumocystis jirovecii is an AIDSdefining illness, and there is a direct inverse relationship between CD4+ T-cell counts in the blood and the risk for infection [1]
To evaluate the immune memory recall responses to Pneumocystis pneumonia, we first investigated the requirement of CD4+ T-cells during secondary immune responses, as well as establishment of cellular and humoral immune memory
Pneumocystis pneumonia is a major cause of morbidity and mortality among immunocompromised patients, especially in the context of HIV/ AIDS
Summary
Pneumonia due to the opportunistic human fungal pathogen Pneumocystis jirovecii is an AIDSdefining illness, and there is a direct inverse relationship between CD4+ T-cell counts in the blood and the risk for infection [1]. Pneumocystis is a major cause of mortality in patients whose CD4+ T-cell number or function is significantly depressed due to malignancy, chemotherapy, or other immunosuppression [1, 2]. Animal models of immunodeficiency demonstrate that the loss of CD4+ T-cells renders mammals susceptible to Pneumocystis lung infection [2]. Frontiers in Immunology | www.frontiersin.org de la Rua et al. Secondary Immune Responses to Pneumocystis from Pneumocystis-infected mice are able to mediate clearance of Pneumocystis infection upon adoptive transfer into Rag1(−/−) mice [3]. CD4+ T-cells have been a primary focus in the study of host defense against this pathogen
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