Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance.Whereas the pivotal role of dendritic cells in determining the balance between immunopathology ...Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance.Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established,we determined that epithelial cells(ECs)also contributes to this balance.Mechanistically,EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon(TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase(IDO)via non-canonical nuclear factor-kB activation.Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis,bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice,underexpressed the IDO-dependent T helper 1/regulatory T cell(Th1/Treg)pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs.Further studies with interferon(IFN)-c,IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-c/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth.Thus,distinct immune pathways contribute to resistance and tolerance to the fungus,to which the hematopoietic/non-hematopoietic compartments contribute through distinct,yet complementary,roles.展开更多
基金by the Specific Targeted Research Project‘Sybaris’(LSHE-CT-2006),contract number 037899(FP7)by the Italian Projects PRIN 2007KLCKP8_004(to LR)and 2007XYB9T9_001(to SB).CC and AC were financially supported by fellowships from Fundac¸a˜o para a Cieˆncia e Tecnologia,Portugal(contracts SFRH/BD/65962/2009 and SFRH/BPD/46292/2008,respectively).
文摘Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance.Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established,we determined that epithelial cells(ECs)also contributes to this balance.Mechanistically,EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon(TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase(IDO)via non-canonical nuclear factor-kB activation.Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis,bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice,underexpressed the IDO-dependent T helper 1/regulatory T cell(Th1/Treg)pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs.Further studies with interferon(IFN)-c,IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-c/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth.Thus,distinct immune pathways contribute to resistance and tolerance to the fungus,to which the hematopoietic/non-hematopoietic compartments contribute through distinct,yet complementary,roles.
