title: Protective role of T-bet and Th1 cytokines in pulmonary graft-versus-host disease and peribronchiolar fibrosis.
abstract: T-box expressed in T cells (T-bet) is a critical transcription factor for T helper (Th) 1 responses. Although Th1 cells are thought to contribute to certain alloimmune responses, their role in pulmonary graft-versus-host disease (GVHD) is uncertain. We have established a murine model of acute pulmonary GVHD after hematopoietic cell transplant (HCT) and inhaled LPS exposure. We tested the hypothesis that pulmonary GVHD can occur independent of Th1 cells using T-bet-deficient donors. B10.BR(H2(k)) mice underwent allogeneic (Allo) or syngeneic (Syn) HCT with cells from either C57Bl/6J(H2(b)) mice (Allo wild-type [WT] or SynWT) or C57Bl/6J mice lacking T-bet (AlloTbet(-/-) or SynTbet(-/-)). After HCT, mice were exposed daily to aerosolized LPS and subsequently bronchoalveolar lavage and lung tissue were analyzed for cytokines, lymphocytic inflammation, pathology, and fibrosis. Independent of LPS exposure, AlloTbet(-/-) mice developed pulmonary GVHD manifested by lymphocytic inflammation. Furthermore, AlloTbet(-/-) mice developed features of chronic pulmonary GVHD, including increased peribronchiolar fibrosis and collagen content. LPS exposure increased neutrophil recruitment and decreased static compliance in AlloTbet(-/-) mice as compared with LPS-exposed AlloWT mice or LPS-exposed SynTbet(-/-) mice. In addition, LPS-exposed AlloTbet(-/-) mice had increased pulmonary IL-17, IL-13, and Th17 cells, and diminished regulatory T cells compared with the other groups. Our results demonstrate that Th1 cytokines are dispensable in pulmonary GVHD. In the absence of T-bet, there is increased production of Th17 and Th2 cytokines that is associated with peribronchiolar fibrosis and is further enhanced by LPS. These results suggest that the interplay between local innate immunity and non-Th1 T cell subsets contribute to chronic pulmonary GVHD.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA. kymberly.gowdy@nih.gov
authors.forename: Kymberly M
authors.initials: KM
authors.lastname: Gowdy
authors.forename: Julia L
authors.initials: JL
authors.lastname: Nugent
authors.forename: Tereza
authors.initials: T
authors.lastname: Martinu
authors.forename: Erin
authors.initials: E
authors.lastname: Potts
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Snyder
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
mesh_terms: D000818:Animals; D055745:Bronchioles / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000503:physiopathology*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000503:physiopathology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D008171:Lung Diseases / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets
chemical_list: D016207:Cytokines