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Interferon- Regulates Idiopathic Pneumonia Syndrome, a Th17⁺CD4⁺ T-Cell–mediated Graft-versus-Host Disease

¹ Experimental Critical Care Medicine, Departments of Research and Internal Medicine, and ² Department of Pathology, University Hospital, Basel, Switzerland; ³ Institute for Immunology and Transfusion Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany; and ⁴ Respiratory Medicine, and ⁵ Emergency Department, University Hospital, Basel, Switzerland

Correspondence and requests for reprints should be addressed to Lukas Hunziker, M.D., Department of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail: lhunziker{at}uhbs.ch

Rationale: Pulmonary complications of hematopoietic stem cell transplantation include infections and graft-versus-host diseases, such as idiopathic pneumonia syndrome (IPS). Conflicting data exist regarding the role of the interferon (IFN)-–producing Th1 CD4⁺ T-cell subset and IL-17A in IPS.

Objectives: To determine the role of IFN- and IL-17A in the establishment of pulmonary graft-versus-host disease.

Methods: A semiallogeneic murine model based on C57BL/6 x BALB/c as recipients with transplantation of BALB/c RAG2^–/– bone marrow and transfer of different genetic knockout T cells (T-bet^–/–, IFN-^–/–, IFN-R^–/–) on a BALB/c background. Lung tissue was examined for parenchymal changes and infiltrating cells by histology and fluorescence-activated cell sorter analysis.

Measurements and Main Results: After transfer of semiallogeneic bone marrow together with donor CD4⁺ T cells lacking IFN- or T-bet—a T-box transcription factor controlling Th1 commitment—we found severe inflammation in the lungs, but no enhancement in other organs. In contrast, wild-type donor CD4⁺ T cells mediated minimal inflammation only, and donor CD8⁺ T cells were not required for IPS development. Mechanistically, the absence of IFN- or IFN- signaling in pulmonary parenchymal cells promoted expansion of IL-17A–producing CD4⁺ T cells and local IL-17A release. In vivo depletion of IL-17A reduced disease severity.

Conclusions: One mechanism of IFN- protection against IPS is negative regulation of the expansion of pathogenic IL-17A–producing CD4⁺ T cells through interaction with the IFN- receptor on the pulmonary parenchymal cell population.

Key Words: idiopathic pneumonia syndrome • graft-versus-host disease • CD4 T cells • IL-17 • antigen-presenting cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Idiopathic pneumonia syndrome is a manifestation of pulmonary graft-versus-host disease that is T-cell mediated, but the nature of the pathologic T-cell response remains obscure. What This Study Adds to the Field We provide evidence that idiopathic pneumonia syndrome is mediated by IL-17–producing T-helper cells and that IFN- signaling is required to suppress this pathologic T-cell subset.

 

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