title: CD8(+)IL-17(+) T Cells Mediate Neutrophilic Airway Obliteration in T-bet-Deficient Mouse Lung Allograft Recipients.
abstract: Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet(-/-) recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T-bet(-/-) recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8(+) T cells producing allospecific IL-17 and/or IFN-γ, in contrast to IFN-γ-dominant responses in WT mice. CD4(+) T cells produced IL-17 but not IFN-γ responses in T-bet(-/-) recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8(+)IFN-γ(+) responses in both T-bet(-/-) and WT mice but had no attenuating effect on lung rejection pathology in T-bet(-/-) recipients or on the development of obliterative airway inflammation that occurred only in T-bet(-/-) recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade-resistant rejection pathology and airway inflammation in T-bet(-/-) recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet(-/-) allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet-deficient recipients of complete MHC-mismatched lung allografts develop costimulation blockade-resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8(+)IL-17(+) T cells. Our data support T-bet-deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation.
authors.affiliation: 1 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Lendermon
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Dodd-o
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Coon
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Miller
authors.forename: Sudipto
authors.initials: S
authors.lastname: Ganguly
authors.forename: Iulia
authors.initials: I
authors.lastname: Popescu
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
authors.forename: Nayra
authors.initials: N
authors.lastname: Cardenes
authors.forename: Melanie
authors.initials: M
authors.lastname: Levine
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Nathaniel M
authors.initials: NM
authors.lastname: Weathington
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.forename: John F
authors.initials: JF
authors.lastname: McDyer
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006648:Histocompatibility; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects*; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D000906:Antibodies; C098680:Il17a protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D023201:CD40 Ligand; D007371:Interferon-gamma
keywords: IL-17; T-bet; acute rejection; mouse orthotopic lung transplant; neutrophils