title: CD4(+) T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease.
abstract: Aspergillus fumigatus is a model fungal pathogen and a common cause of infection in individuals with the primary immunodeficiency chronic granulomatous disease (CGD). Although primarily considered a deficiency of innate immunity, CGD is also linked to dysfunctional T cell reactivity. Both CD4(+) and CD8(+) T cells mediate vaccine-induced protection from experimental aspergillosis, but the molecular mechanisms leading to the generation of protective immunity and whether these mechanisms are dysregulated in individuals with CGD have not been determined. Here, we show that activation of either T cell subset in a mouse model of CGD is contingent upon the nature of the fungal vaccine, the involvement of distinct innate receptor signaling pathways, and the mode of antigen routing and presentation in DCs. Aspergillus conidia activated CD8(+) T cells upon sorting to the Rab14(+) endosomal compartment required for alternative MHC class I presentation. Cross-priming of CD8(+) T cells failed to occur in mice with CGD due to defective DC endosomal alkalinization and autophagy. However, long-lasting antifungal protection and disease control were successfully achieved upon vaccination with purified fungal antigens that activated CD4(+) T cells through the endosome/lysosome pathway. Our study thus indicates that distinct intracellular pathways are exploited for the priming of CD4(+) and CD8(+) T cells to A. fumigatus and suggests that CD4(+) T cell vaccination may be able to overcome defective antifungal CD8(+) T cell memory in individuals with CGD.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Remi
authors.initials: R
authors.lastname: Beau
authors.forename: Andrea
authors.initials: A
authors.lastname: Casagrande
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.forename: Gloria
authors.initials: G
authors.lastname: Giovannini
authors.forename: Cristina
authors.initials: C
authors.lastname: Massi-Benedetti
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latgé
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology*; D001228:Aspergillosis / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D045142:Cross-Priming; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000628:therapy; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use; D010587:Phagocytosis; D015398:Signal Transduction; D013172:Spores, Fungal / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000946:Antigens, Fungal; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C518330:RUVBL2 protein, mouse