Interferon-gamma regulates idiopathic pneumonia syndrome, a Th17+CD4+ T-cell-mediated graft-versus-host disease.
BACKGROUND
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)-gamma-producing Th1 CD4(+) T-cell subset and IL-17A in IPS.


OBJECTIVE
To determine the role of IFN-gamma 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-gamma(-/-), IFN-gammaR(-/-)) on a BALB/c background. Lung tissue was examined for parenchymal changes and infiltrating cells by histology and fluorescence-activated cell sorter analysis.


RESULTS
After transfer of semiallogeneic bone marrow together with donor CD4(+) T cells lacking IFN-gamma 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-gamma or IFN-gamma 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-gamma protection against IPS is negative regulation of the expansion of pathogenic IL-17A-producing CD4(+) T cells through interaction with the IFN-gamma receptor on the pulmonary parenchymal cell population.
Departments of Research and Internal Medicine, Experimental Critical Care Medicine, University Hospital, Basel, Switzerland.
Nora
N
Mauermann
Julia
J
Burian
Christophe
C
von Garnier
Stefan
S
Dirnhofer
Davide
D
Germano
Christine
C
Schuett
Michael
M
Tamm
Roland
R
Bingisser
Urs
U
Eriksson
Lukas
L
Hunziker
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology*; D020381:Interleukin-17 / Q000097:blood*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D017471:Receptors, Interferon / Q000502:physiology; D013577:Syndrome; D020825:T-Box Domain Proteins / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology*; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor
D007371:Interferon-gamma; D020381:Interleukin-17; D017471:Receptors, Interferon; D020825:T-Box Domain Proteins; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor; C098680:Il17a protein, mouse