Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/23919

TitleCD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease
Author(s)Luca, Antonella De
Iannitti, Rossana G.
Bozza, Silvia
Beau, Remi
Casagrande, Andrea
D’Angelo, Carmen
Moretti, Silvia
Cunha, Cristina
Giovannini, Gloria
Massi-Benedetti, Cristina
Carvalho, Agostinho
Boon, Louis
Latgé, Jean-Paul
Romani, Luigina
Issue dateMay-2012
PublisherAmerican Society for Clinical Investigation
JournalJournal of Clinical Investigation
Abstract(s)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.
TypeArticle
URIhttp://hdl.handle.net/1822/23919
DOI10.1172/JCI60862
ISSN0021-9738
Publisher versionhttp://dx.doi.org/10.1172%2FJCI60862
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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