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Pneumocystis Cell Wall -Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism¹

Eva M. Carmona^*, Robert Vassallo^*, Zvezdana Vuk-Pavlovic^*, Joseph E. Standing^*, Theodore J. Kottom^* and Andrew H. Limper^2,*,

^* Thoracic Diseases Research Unit, Division of Pulmonary Critical Care and Internal Medicine, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905; and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905

Respiratory failure during Pneumocystis pneumonia is mainly a consequence of exaggerated inflammatory responses to the organism. Dendritic cells (DCs) are the most potent APCs in the lung and are key to the regulation of innate and adaptive immune responses. However, their participation in the inflammatory response directed against Pneumocystis infection has not been fully elucidated. Therefore, we studied the role of Pneumocystis carinii, as well as Saccharomyces cerevisiae, cell wall-derived -glucans, in DC costimulatory molecule expression. We further studied the impact of -glucans on subsequent T cell activation. Because cytokine secretion by DCs has recently been shown to be regulated by Fas ligand (FasL), its role in -glucan activation of DCs was also investigated. -Glucan-induced DC activation occurred in part through dectin-1 receptors. We demonstrated that DC activation by -glucans elicits T cell activation and polarization into a Th1 patterned response, but with the conspicuous absence of IL-12. These observations differed from LPS-driven T cell polarization, suggesting that -glucans and LPS signal DC activation through different mechanisms. We additionally determined that IL-1 and TNF- secretion by -glucan-stimulated DCs was partially regulated by Fas-FasL. This suggests that dysregulation of FasL could further enhance exuberant and prolonged cytokine production by DCs following DC-T cell interactions, further promoting lung inflammation typical of Pneumocystis pneumonia.

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