c Pneumocystis is a respiratory fungal pathogen that causes pneumonia (Pneumocystis pneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4؉ T cell-dependent clearance of Pneumocystis, and previous studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement for either classically or alternatively activated macrophages for Pneumocystis clearance has not been determined. Therefore, RAG2؊/؊ mice lacking either the interferon gamma (IFN-␥) receptor (IFN-␥R) or interleukin 4 receptor alpha (IL-4R␣) were infected with Pneumocystis. These mice were then immune reconstituted with wild-type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2 cell responses in RAG/IFN-␥R؊/؊ mice were associated with elevated lung IFN-␥ levels, and neutralization of IFN-␥ restored the CD8 response. These data demonstrate that restricting the ability of macrophages to polarize in response to Th1 or Th2 cytokines does not impair Pneumocystis clearance. However, a cell type-specific IFN-␥/IFN-␥R-dependent mechanism regulates CD8 ؉ T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcPrelated IRIS. Pneumocystis is an opportunistic fungal pathogen, which is widespread throughout the human population. Vargas et al. reported that nearly 85% of children have been exposed to Pneumocystis by 20 months of age (1). The infection appears mild and self-limited in a normal host, but Pneumocystis causes life-threatening pneumonia in patients with defects in cell-mediated immunity. Pneumocystis pneumonia (PcP) remains prevalent in those with AIDS (2) and is a leading cause of death in HIV-infected patients, with a mortality rate of up to 50% in those with severe disease (3). Pneumocystis also infects patients receiving long-term immunomodulatory therapy for rheumatoid arthritis and other inflammatory diseases (4) as well as cancer patients undergoing chemotherapy (5). Furthermore, Pneumocystis infection or colonization has been associated with chronic obstructive pulmonary disease in both HIV and non-HIV patients (6).Despite the availability of antibiotics that effectively eradicate Pneumocystis, rapid clinical improvement is not always observed in patients with PcP. The host's immune response against this pathogen often contributes to severe PcP-related lung injury (6, 7). Clinical studies suggest that the intensity of pulmonary inflammation, rather than organism lung burden, correlates with the severity of PcP (8-10). Furthermore, rapid and unbalanced restoration of cell-mediated immunity following antiretroviral treatment of Pneumocystis-infected HIV patients sometimes results in exaggerated lung inflammation and leads to the clinical manifestation of immune reconstitution inflammatory syndrome (IRIS) (11). IRIS is an...

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Pneumocystis is a respiratory fungal pathogen that is among the most frequent causes of life-threatening pneumonia (PcP) in immunocompromised hosts. Alveolar macrophages play an important role in host defense against Pneumocystis , and several studies have suggested that M2 polarized macrophages have anti- Pneumocystis effector activity.