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Departments of
*
Pediatrics and
Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
CD8+ T cells contribute to the pathophysiology of Pneumocystis pneumonia (PcP) in a murine model of AIDS-related disease. The present studies were undertaken to more precisely define the mechanisms by which these immune cells mediate the inflammatory response that leads to lung injury. Experimental mice were depleted of either CD4+ T cells or both CD4+ and CD8+ T cells and then infected with Pneumocystis. The CD4+-depleted mice had significantly greater pulmonary TNF-
levels than mice depleted of both CD4+ and CD8+ T cells. Elevated TNF- levels were associated with increased lung concentrations of the chemokines RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant. To determine whether TNFR signaling was involved in the CD8+ T cell-dependent chemokine response, TNFRI- and II-deficient mice were CD4+ depleted and infected with Pneumocystis. TNFR-deficient mice had significantly reduced pulmonary RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant responses, reduced inflammatory cell recruitment to the alveoli, and reduced histological evidence of PcP-related alveolitis as compared with infected wild-type mice. Diminished pulmonary inflammation correlated with improved surfactant activity and improved pulmonary function in the TNFR-deficient mice. These data indicate that TNFR signaling is required for maximal CD8+ T cell-dependent pulmonary inflammation and lung injury during PcP and also demonstrate that CD8+ T cells can use TNFR signaling pathways to respond to an extracellular fungal pathogen.
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