CD8+IL-17+ T cells mediate neutrophilic airway obliteration in T-bet-deficient mouse lung allograft recipients

Elizabeth A. Lendermon, Jeffrey M. Dodd-O, Tiffany A. Coon, Hannah L. Miller, Sudipto Ganguly, Iulia Popescu, Christopher P. O'Donnell, Nayra Cardenes, Melanie Levine, Mauricio Rojas, Nathaniel M. Weathington, Jing Zhao, Yutong Zhao, John F. McDyer

Research output: Contribution to journalArticle

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 IIN-γ responses in T-bet-/- recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8+IFN-7+ responses in both T-bet-/- and W 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.

Original languageEnglish (US)
Pages (from-to)622-633
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume52
Issue number5
DOIs
StatePublished - May 1 2015

Keywords

  • Acute rejection
  • IL-17
  • Mouse orthotopic lung transplant
  • Neutrophils
  • T-bet

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    Lendermon, E. A., Dodd-O, J. M., Coon, T. A., Miller, H. L., Ganguly, S., Popescu, I., O'Donnell, C. P., Cardenes, N., Levine, M., Rojas, M., Weathington, N. M., Zhao, J., Zhao, Y., & McDyer, J. F. (2015). CD8+IL-17+ T cells mediate neutrophilic airway obliteration in T-bet-deficient mouse lung allograft recipients. American journal of respiratory cell and molecular biology, 52(5), 622-633. https://doi.org/10.1165/rcmb.2014-0059OC