Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis

Delamarre, Lélia; Couture, Rachael; Mellman, Ira; Trombetta, E. Sergio

doi:10.1083/jcb1745oia9

Cited by 37 publications

(51 citation statements)

References 10 publications

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“…Its degradative capacity needs to be re-tuned to maximize proteolysis for epitope production and not for total degradation. Consistent with this rationale is the finding that two isoforms of two different protein antigens, RNase and horseradish peroxidase, which, by virtue of intra-chain cleavages, differ markedly in their susceptibility to degradation following endocytosis37. Following inoculation of mice with the different isoforms of each protein absorbed onto an adjuvant (alum), the isoforms of each protein that was less susceptible to degradation, and therefore more persistant, were found to be more immunogenic.…”

Section: Immune Modulation Of the Intraphagosomal Milieumentioning

confidence: 87%

The macrophage marches on its phagosome: dynamic assays of phagosome function

et al. 2009

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Section: Immune Modulation Of the Intraphagosomal Milieumentioning

confidence: 87%

The macrophage marches on its phagosome: dynamic assays of phagosome function

et al. 2009

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“…Studies from Delamarre et al. and Egger et al. suggest that resistance to lysosomal proteolysis is determinant in the immunogenicity of proteins by favoring efficient and long‐lasting antigen presentation in draining lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

Heat processing of peanut seed enhances the sensitization potential of the major peanut allergen Ara h 6

Guillon

Bernard

Drumare

et al. 2016

Mol. Nutr. Food Res.

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ScopeProcessing of food has been shown to impact IgE binding and functionality of food allergens. In the present study, we investigated the impact of heat processing on the sensitization capacity of Ara h 6, a major peanut allergen and one of the most potent elicitors of the allergic reaction.Methods and resultsPeanut extracts obtained from raw or heat‐processed peanut and some fractions thereof were biochemically and immunochemically characterized. These extracts/fractions, purified Ara h 6, or recombinant Ara h 6 including Ara h 6 mutants lacking disulfide bridges were used in in vitro digestion tests and mouse models of experimental sensitization. Peanut roasting led to the formation of complexes of high molecular weight, notably between Ara h 6 and Ara h 1, which supported the induction of IgE specific to native Ara h 6. On the contrary, a fraction containing free monomeric 2S albumins or purified native Ara h 6 displayed no intrinsic allergenicity. In addition to complex formation, heat denaturation and/or partial destabilization enhanced Ara h 6 immunogenicity and increased its sensitivity to digestion.ConclusionThese results suggest that sensitization potency and IgE binding capacity can be supported by different structures, modified and/or produced during food processing in interaction with other food constituents.

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“…In addition, Delamarre et al have demonstrated that antigens more resistant to lysosomal proteases result in greater immunogenicity in vivo [33]. Weak bases such as chloroquine and NH 4 Cl, which inhibit phagosomal acidification, have been shown to enhance cross-presentation in vivo , leading to effective CTL responses against viral infections [34].…”

Section: Discussionmentioning

confidence: 99%

The role of phagosomal pH on the size-dependent efficiency of cross-presentation by dendritic cells

Tran

Shen

2009

Biomaterials

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Vaccines able to stimulate CD8+T cells are crucial in controlling a broad range of infectious diseases and tumors. To induce effective CD8+T cell responses, exogenous antigen has to be cross-presented onto major histocompatibility complex (MHC) class I molecules by dendritic cells. Although particle size has been recognized as a critical factor of vaccine design, it is unclear how the size of vaccine carriers impacts the intracellular processing of exogenous antigen and cross-presentation onto MHC class I molecules. In this study, by using polystyrene beads with narrowly defined sizes as model antigen carriers, we demonstrate that particle size mediates the efficiency of cross-presentation of exogenous antigens. By examining the intracellular trafficking, kinetics of phagosomal pH and degradation of antigens bounded to beads, we illustrate the possible mechanisms attributed to the profound effect of particle size on the efficiency of cross-presentation. Antigen bounded to 50 nm beads was shuttled rapidly to an acidic environment within half an hour post-exposure to cells, leading to its rapid and unregulated degradation and inefficient cross-presentation. In contrast, antigen bounded to 500 nm and 3 μm beads remained in a more neutral environment, which preserved the majority of antigens, leaving it available for the generation of peptides to be loaded onto MHC class I molecules. We conclude that the size of antigen carriers plays a critical role in directing antigen to the class I antigen presentation pathway. Our results, together with previous in vivo studies on the effect of particle size on CD8+T cell responses, provide insight into the rational design of vaccines for the stimulation of cell-mediated immunity.

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Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis

Cited by 37 publications

References 10 publications

The macrophage marches on its phagosome: dynamic assays of phagosome function

The macrophage marches on its phagosome: dynamic assays of phagosome function

Heat processing of peanut seed enhances the sensitization potential of the major peanut allergen Ara h 6

The role of phagosomal pH on the size-dependent efficiency of cross-presentation by dendritic cells

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