title: TLR3 essentially promotes protective class I-restricted memory CD8⁺ T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients.
abstract: Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8⁺ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8⁺ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4⁺ and CD8⁺ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8⁺ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8⁺ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8⁺ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, Perugia, Italy.
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.forename: Katia
authors.initials: K
authors.lastname: Perruccio
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Antonio
authors.initials: A
authors.lastname: Pierini
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latgé
authors.forename: Andrea
authors.initials: A
authors.lastname: Velardi
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000946:Antigens, Fungal / Q000627:therapeutic use; D001228:Aspergillosis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D001232:Aspergillus fumigatus / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D005657:Fungal Vaccines / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016867:Immunocompromised Host; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D013047:Specific Pathogen-Free Organisms; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000946:Antigens, Fungal; D005657:Fungal Vaccines; D051196:Toll-Like Receptor 3