Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO.
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-κB 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)-γ, IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-γ/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.
de Luca
Antonella
A
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Bozza
Silvia
S
Zelante
Teresa
T
Zagarella
Silvia
S
D'Angelo
Carmen
C
Perruccio
Katia
K
Vacca
Carmine
C
Carvalho
Agostinho
A
Cunha
Cristina
C
Aversa
Franco
F
Romani
Luigina
L
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology*; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D018380:Hematopoietic Stem Cell Transplantation; D006413:Hematopoietic System / Q000166:cytology* / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007737:Kynurenine / Q000494:pharmacology; D051379:Mice; D011014:Pneumonia / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D055732:Pulmonary Aspergillosis / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D033942:Adaptor Proteins, Vesicular Transport; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D020381:Interleukin-17; D007737:Kynurenine; D053722:Receptors, Interleukin-17; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse