title: Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism.
abstract: The inherent resistance to diseases caused by Aspergillus fumigatus suggests the occurrence of regulatory mechanisms that provide the host with adequate defense without necessarily eliminating the fungus or causing unacceptable levels of host damage. In this study, we show that a division of labor occurs between functionally distinct regulatory T cells (Treg) that are coordinately activated by a CD28/B-7-dependent costimulatory pathway after exposure of mice to Aspergillus conidia. Early in infection, inflammation is controlled by the expansion, activation and local recruitment of CD4+CD25+ Treg capable of suppressing neutrophils through the combined actions of IL-10 and CTLA-4 on indoleamine 2,3-dioxygenase. The levels of IFN-gamma produced in this early phase set the subsequent adaptive stage by conditioning the indoleamine 2,3-dioxygenase-dependent tolerogenic program of dendritic cells and the subsequent activation and expansion of tolerogenic Treg, which produce IL-10 and TGF-beta, inhibit Th2 cells, and prevent allergy to the fungus. The coordinate activation of Treg may, however, be subverted by the fungus, as germinating conidia are capable of interfering with anti-inflammatory and tolerogenic Treg programs. Thus, regulation is an essential component of the host response in infection and allergy to the fungus, and its manipulation may allow the pathogen to overcome host resistance and promote disease.
authors.affiliation: Department of Experimental Medicine and Biochemical Science, University of Perugia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Montagnoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Roberta
authors.initials: R
authors.lastname: Gaziano
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Silvia
authors.initials: S
authors.lastname: Bellocchio
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.forename: Wiswanath P
authors.initials: WP
authors.lastname: Kurup
authors.forename: Lucia
authors.initials: L
authors.lastname: Pitzurra
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics; D051940:B7-2 Antigen / Q000235:genetics; D018106:CD28 Antigens / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D004198:Disease Susceptibility; D005260:Female; D006967:Hypersensitivity / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D007111:Immunity, Cellular; D007113:Immunity, Innate; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan