Abstract
Obliterative bronchiolitis (OB) is immune mediated fibrous obliteration of the small airways and limits long term lung transplant survival. Previous studies in a mouse model of minor MHC mismatch orthotopic left lung transplant (C57Bl/10, H-2b®C57Bl/6, H-2b) have suggested a role for IL-17A, a pro-inflammatory and pro-fibrotic cytokine, in OB development. However, the mechanisms by which IL-17A induce OB are not known. Here, we have investigated the cellular sources of IL-17A and determined their contribution to OB development in this model using antibody mediated depletion of T cells and conditional knockout mice. We found increased infiltration of IL-17A+ lymphocytes in left lung allografts at 21 days after transplant. The infiltration of IL-17A+ lymphocytes coincided with OB development. IL-17A was produced by CD4+ T cells (Th17) and gδT cells. IL-17A+ T cell subsets were higher in allografts than isografts. Depletion of CD4+ T cells abrogated OB development and led to impaired IL-17A+ lymphocyte responses in allografts. To further test if IL-17A+ CD4 T cells (Th17) were required for OB development, left lungs were transplanted from C57Bl/10 mice to conditional knockout C57Bl/6 STAT3fl/fl mice with a CD4-Cre transgene (STAT3CD4-/-). The CD4+ T cells from STAT3CD4-/- mice are not able to differentiate into Th17 cells because of lack of STAT3. Contrary to expectations, the lung allografts from STAT3CD4-/- mice demonstrated OB lesions. The frequency of IL-17A+ lymphocytes was not decreased in allografts from Th17 deficient mice and gδ T cells remained a major source of IL-17A. Our data suggest that CD4+ T cells are required for OB whereas Th17 cells are not necessary for OB. Our data may support the use of immunosuppressive strategies targeting CD4+ T cells to extend lung allograft survival in clinical settings. Supported by NIH (R01HL109310).
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