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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 2

p47phox–/– mice fail to develop MHC class I–restricted CD8+ T cell responses to Aspergillus conidia.

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p47phox–/– mice fail to develop MHC class I–restricted CD8+ T cell resp...
Mice (6/group) received conidia or Pep1p plus CpG as described for Figure 1 and were concomitantly treated with the indicated antibodies or an isotype-matched control antibody (None). Fungal growth (log10 CFU ± SEM) in conidia-vaccinated (A) or Pep1p-vaccinated (B) mice at 3 days after reinfection. Control (Ct), infected, unvaccinated mice. Pooled data from 3 experiments are shown. (C) Lung immunohistochemistry 3 days after reinfection. Cell surface markers were Alexa Fluor 488–anti-CD4 and Alexa Fluor 647–anti-CD8 antibody. Cell nuclei were stained with DAPI (blue). Representative pictures (of 3 experiments) were taken with an original magnification of ×200. (D) Proliferation of CD4+ and CD8+ T cells purified from lungs 1 week after a primary i.n. infection. DNA synthesis was measured by 3H-thymidine uptake after 72 hours coculture with conidia- or Pep1p-pulsed DCs from the corresponding naive mice. Ct, T cells alone. Relative expression of (E) Ifng and (F) Prf1 by RT-PCR in CD4+ and CD8+ T cells exposed to conidia- or Pep1p-pulsed DCs for 24 hours. (G) Cytolytic activity of CD8+ T cells, obtained as in D, against conidia-pulsed DCs at different E/T ratios. Shown is the percentage of specific cytotoxic activity determined by a standard 4-hour 51Cr-release assay. (H) Conidiocidal activity of culture supernatants from CD8+ T cells exposed as in D (visualized with an original magnification of ×400). Activation/memory marker expression (I) and intracellular cytokine staining (J) by lung CD8+ and CD4+ T cells purified from conidia- or Pep1p-vaccinated mice, respectively, 3 days after reinfection. Histograms were generated from pooled samples of 6 mice/group. Representative histograms from a single experiment are shown. Values are the percentages of positive cells. *P < 0.05, **P < 0.01, ***P < 0.001 treated versus untreated mice (A and B) and pulsed DC–stimulated versus unstimulated cells (None) (D–G).

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

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