CD4+ T Cells and Not Th17 Cells Are Required for Lung Transplant Obliterative Bronchiolitis.

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).