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Th17-Polarized Immune Response in a Murine Model of Hypersensitivity Pneumonitis and Lung Fibrosis¹

Philip L. Simonian^2,*, Christina L. Roark, Fabian Wehrmann^*, Allison K. Lanham^*, Fernando Diaz del Valle^*, Willi K. Born, Rebecca L. O’Brien and Andrew P. Fontenot^*,

^* Department of Medicine, University of Colorado Denver, Denver, CO 80262; and Integrated Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206

Hypersensitivity pneumonitis is an environmental lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. Using a well-established murine model of hypersensitivity pneumonitis, we repeatedly exposed C57BL/6 mice to Saccharopolyspora rectivirgula to investigate whether T cells are required for lung fibrosis. In the absence of β T cells, TCRβ^–/– mice exposed to S. rectivirgula for 4 wk had markedly decreased mononuclear infiltrates and collagen deposition in the lung compared with wild-type C57BL/6 mice. In contrast to CD8⁺ T cells, adoptive transfer of CD4⁺ T cells reconstituted the S. rectivirgula-induced inflammatory and fibrotic response, suggesting that the CD4⁺ T cell represents the critical β T cell subset. Cytokine analysis of lung homogenates at various time points after S. rectivirgula exposure failed to identify a predominant Th1 or Th2 phenotype. Conversely, IL-17 was found in the lung at increasing concentrations with continued exposure to S. rectivirgula. Intracellular cytokine staining revealed that 14% of CD4⁺ T cells from the lung of mice treated with S. rectivirgula expressed IL-17A. In the absence of IL-17 receptor signaling, Il17ra^–/– mice had significantly decreased lung inflammation and fibrosis compared with wild-type C57BL/6 mice. These data are the first to demonstrate an important role for Th17-polarized CD4⁺ T lymphocytes in the immune response directed against S. rectivirgula in this murine model of hypersensitivity pneumonitis and pulmonary fibrosis.

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 This work was supported by National Institutes of Health Grants HL62410 and ES011810 (to A.P.F.) and HL89766 (to P.L.S.).

² Address correspondence and reprint requests to Dr. Philip L. Simonian, Divisions of Clinical Immunology and Pulmonary Sciences/Critical Care Medicine (B164), University of Colorado Denver, 4200 East Ninth Avenue, Denver, CO 80262. E-mail address: philip.simonian{at}ucdenver.edu

³ Abbreviations used in this paper: HP, hypersensitivity pneumonitis; wt, wild type.

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