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)-γ–producing Th1 CD4⁺ T-cell subset and IL-17A in IPS.

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

Methods: A semiallogeneic murine model based on C57BL/6 × BALB/c as recipients with transplantation of BALB/c RAG2^−/− bone marrow and transfer of different genetic knockout T cells (T-bet^−/−, IFN-γ^−/−, IFN-γR^−/−) 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-γ 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-γ or IFN-γ 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-γ protection against IPS is negative regulation of the expansion of pathogenic IL-17A–producing CD4⁺ T cells through interaction with the IFN-γ receptor on the pulmonary parenchymal cell population.