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CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung

Abstract

CD1d-restricted T cells are implicated as key players in host defense against various microbial infections. However, the mechanisms involved and the role they play, if any, at the mucosal surfaces where pathogenic infections are initiated is unknown. In a murine pneumonia model established by intranasal application of Pseudomonas aeruginosa, CD1d−/− mice showed markedly reduced pulmonary eradication of P. aeruginosa compared with wild-type mice; this was associated with significantly lower amounts of macrophage inflammatory protein-2 and reduced numbers of neutrophils within the bronchoalveolar lavage fluid. Corollarily, treatment of mice with α-galactosylceramide—a lipid that activates CD1d-restricted T cells—increased the amount of interferon-γ; this was associated with rapid pulmonary clearance through enhanced phagocytosis of P. aeruginosa by alveolar macrophages. These results reveal a crucial role played by CD1d-restricted T cells in regulating the antimicrobial immune functions of macrophages at the lung mucosal surface.

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Acknowledgements

We thank S. Shapiro for helpful discussions; I. Wang for technical support; and Kirin Pharmaceuticals for generously providing the glycolipids we used. R.S.B. was supported by NIH grants DK44319, DK51362 and DK53056 and the Harvard Digestive Diseases Center. S.P.C. was supported by grant PO1 DE 13499. E.E.S.N. was supported by the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences.

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The authors declare no competing financial interests.

Correspondence to Richard S. Blumberg.

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Figure 1: CD1d-dependent clearance of P. aeruginosa from the lungs.
Figure 2: Treatment with αGalCer greatly enhances clearance of P. aeruginosa in acute pneumonia model.
Figure 3: Treatment with αGalCer leads to rapid recovery from P. aeruginosa pneumonia.
Figure 4: αGalCer activates macrophages through CD1d-restricted T-cell activation.
Figure 5: Activation of AMs in the lung by αGalCer.