Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

摘要: Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Whereas pivotal role dendritic cells in determining balance between immunopathology and protective fungus is well established, we determined that epithelial (ECs) also contributes this balance. Mechanistically, EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 domain-containing adaptor-inducing interferon (TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase (IDO) via non-canonical nuclear factor-κB activation. Consistent high susceptibility TRIF-deficient mice pulmonary aspergillosis, bone marrow chimeric TRIF unresponsive ECs exhibited higher fungal burdens inflammatory pathology than control mice, underexpressed IDO-dependent T helper 1/regulatory cell (Th1/Treg) overexpressed Th17 massive neutrophilic inflammation lungs. Further studies (IFN)-γ, IDO or IL-17R confirmed dependency tolerance IFN-γ/IDO/Treg resistance MyD88 controlling growth. Thus, distinct pathways contribute fungus, which hematopoietic/non-hematopoietic compartments distinct, yet complementary, roles.