T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in the development of allograft rejection in an established MHC class II-mismatched (bm12 into B6) model of chronic allograft vasculopathy (CAV). Intriguingly, and in contrast to IFN-γ -/- mice that are protected from CAV, T-bet -/- recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17-producing CD4 T cells. Concurrently, T-bet -/- mice exhibit a T helper type 1 (Thl)-deficient environment characterized by profound IFN-7 deficiency, a Th2 switch characterized by increased production of interleukin (IL) 4, IL-5, IL-10, and IL-13 cytokines, as well as increased production of the proinflammatory cytokines IL-6, IL-12p40, and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection and vasculopathy in T-bet -/- mice. Interestingly, CD4 but not CD8 T cell deficiency in T-bet -/- mice affords dramatic protection from vasculopathy and facilitates long-term graft acceptance. This is the first study establishing that in the absence of Th1-mediated alloimmune responses, CD4 Th17 cells mediate an aggressive proinflamma-tory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for the development of novel therapies to target this intractable problem in clinical solid organ transplantation.
|Titolo:||A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy|
|Parole Chiave:||Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Cytokines; Genes, MHC Class II; Graft Rejection; Heart Transplantation; Immunologic Memory; Interferon-gamma; Mice; Mice, Knockout; Phenotype; STAT4 Transcription Factor; T-Box Domain Proteins; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Transplantation, Homologous; Vascular Diseases; Immunology; Immunology and Allergy; Medicine (all)|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||2008|
|Digital Object Identifier (DOI):||10.1084/jem.20081937|
|Appare nelle tipologie:||01 - Articolo su periodico|