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Regulatory T Cells Dampen Pulmonary Inflammation and Lung Injury in an Animal Model of Pneumocystis Pneumonia¹

Department of Pediatrics, and Division of Pulmonary Medicine, Allergy, and Immunology, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

CD4⁺CD25⁺FoxP3⁺ regulatory T cells are decreased in patients infected with HIV and have been shown to be critical in mediating Ag tolerance in the lung. Because a subset of Pneumocystis-infected individuals develop substantial lung injury, which can be modeled in immune reconstituted scid mice, we used mouse models of Pneumocystis carinii to investigate the role of regulatory T cells in opportunistic infection and immune reconstitution. In this study, we show that CD4⁺CD25⁺FoxP3⁺ cells are part of the host response to Pneumocystis in CD4⁺ T cell-intact mice. Moreover, lung injury and proinflammatory Th1 and Th2 cytokine levels in the bronchoalveolar lavage fluid and lung homogenate were increased following CD4⁺CD25^– immune reconstitution in Pneumocystis-infected SCID mice but not in CD4⁺CD25⁺ T cell-reconstituted animals. The ability of CD4⁺CD25⁺ T cells to control inflammation and injury during the course of Pneumocystis was confirmed by treatment of wild-type C57BL/6 mice with anti-CD25 mAb. These data show that CD4⁺CD25⁺ T cells control pulmonary inflammation and lung injury associated with Pneumocystis infection both in the setting of immune reconstitution as well as new acquisition of infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ J.K.K. acknowledges support from Public Health Service Grants 5R01HL062052 and 5R01HL061271.

² Address correspondence and reprint requests to Dr. Jay K. Kolls, Children’s Hospital of Pittsburgh, Suite 3765, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: jay.kolls{at}chp.edu

³ Abbreviations used in this paper: PCP, Pneumocystis pneumonia; HAART, highly active antiretroviral therapy; WT, wild type; BAL, bronchoalveolar lavage; LDH, lactate dehydrogenase; LN, lymph node; IRIS, immune reconstitution inflammatory syndrome; FoxP3, forkhead transcription factor P3; NR, nonreconstituted.

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