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CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease
Antonella De Luca, … , Jean-Paul Latgé, Luigina Romani
Antonella De Luca, … , Jean-Paul Latgé, Luigina Romani
Published April 23, 2012
Citation Information: J Clin Invest. 2012;122(5):1816-1831. https://doi.org/10.1172/JCI60862.
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Research Article Article has an altmetric score of 6

CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

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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

Antonella De Luca, Rossana G. Iannitti, Silvia Bozza, Remi Beau, Andrea Casagrande, Carmen D’Angelo, Silvia Moretti, Cristina Cunha, Gloria Giovannini, Cristina Massi-Benedetti, Agostinho Carvalho, Louis Boon, Jean-Paul Latgé, Luigina Romani

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Figure 6

CD11b+p47phox–/– DCs efficiently present fungal antigens.

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CD11b+p47phox–/– DCs efficiently present fungal antigens.
   
(A and B) ...
(A and B) Flow cytometry of phagocytosis of live GFP-expressing conidia by lung DCs purified from uninfected mice. Values are percentages of positive cells on T and B cell–depleted lung cells. Phagocytosis was quantified via phase contrast and fluorescence microscopy at ×1,000 magnification (shown are representative microscopy images of 2 independent experiments). (C) Mice were infected i.n. with GFP-expressing A. fumigatus conidia, and the numbers of GFP+CD11c+ cells were assessed by flow cytometry at 3 days after infection. Values are percentages of positive cells on gated CD11c+ cells. DCs purified from lung of naive mice were unpulsed (None) or pulsed with live Aspergillus conidia or Pep1p for (D) 24 hours prior to being assessed for cytokine gene expression by RT-PCR and (E) 2 hours before the assessment of pERK44/42 phosphorylation by immunoblot analysis. Shown is a representative Western blot of 2 independent experiments and corresponding pixel density ratio normalized against β-tubulin (β-tub). (F and G) Adoptive transfer of C57BL/6 or p47phox–/– lung DCs pulsed with conidia or Pep1p into C57BL/6 mice. DCs were adoptively transferred by i.p. injection twice, a week apart, before the i.n. infection. Fungal growth in the lungs (F, log10 CFU ± SEM, representative of at least 3 independent experiments) and histology (G, PAS staining) were determined 3 days after infection. *P < 0.05, **P < 0.01, ***P < 0.001, pulsed versus unpulsed DCs (D) and mice receiving or not (None) DCs (F). Scale bars: 200 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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