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MHC class I antigen cross-presentation mediated by PapMV nanoparticles in human antigen-presenting cells is dependent on autophagy.

ABSTRACT: Nanoparticles made of the coat protein of papaya mosaic virus (PapMV) and a single-strand RNA were previously shown to be an efficient antigen presentation system for the trigger of cellular immunity. Engineering of PapMV nano with a cytotoxic T lymphocyte epitope was previously shown activating specific T lymphocytes through a proteasome-independent major histocompatibility complex class I (MHC-I) cross-presentation. In this study, we provide new insights into the mechanism of the MHC-I cross-presentation mediated by PapMV nanoparticles. We demonstrate that PapMV nanoparticles do not require the transporter associated with antigen presentation (TAP), but rather depend on lysosome acidification and cathepsin S protease activity for presentation of the T cell epitope. We have also linked the induction of autophagy with this vacuolar MHC-I cross-presentation process. Interestingly, autophagy is induced in antigen-presenting cells after PapMV nanoparticles exposure and inhibition of autophagy reduce MHC-I cross-presentation. This study demonstrates that autophagy is associated with TAP- and proteasome-independent MHC-I cross-presentation. A deeper understanding of the autophagy-dependent MHC-I cross-presentation will be useful in designing vaccination platforms that aim to trigger an efficient cytotoxic T lymphocyte response.

SUBMITTER: Possamai D

PROVIDER: S-EPMC8719699 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Macrophages are innate immune cells that internalize and present exogenous antigens to T cells via MHC class II proteins. They operate at sites of infection in a highly inflammatory environment, generated in part by reactive oxygen species, in particular the strong oxidant hypochlorous acid (HOCl) produced in the neutrophil respiratory burst. HOCl effectively kills a broad range of pathogens but can also contribute to host tissue damage at sites of inflammation. To prevent tissue injury, HOCl is scavenged by human serum albumin (HSA) and other plasma proteins in interstitial fluids, leading to the formation of variously modified advanced oxidation products (AOPPs) with pro-inflammatory properties. Previously, we showed that HOCl-mediated N-chlorination converts HSA and other plasma proteins into efficient activators of the phagocyte respiratory burst, but the role of these AOPPs in antigen presentation by macrophages remained unclear. Here, we show that physiologically relevant amounts of N-chlorinated HSA can strongly impair the capacity of THP-1-derived macrophages to present antigens to antigen-specific T cells via MHC class II proteins at multiple stages. Initially, N-chlorinated HSA inhibits antigen internalization by converting antigens into scavenger receptor (SR) ligands and competing with the modified antigens for binding to SR CD36. Later steps of antigen presentation, such as intracellular antigen processing and MHC class II expression are negatively affected, as well. We propose that impaired processing of pathogens or exogenous antigens by immune cells at an initial stage of infection prevents antigen presentation in an environment potentially hostile to cells of the adaptive immune response, possibly shifting it towards locations removed from the actual insult, like the lymph nodes. On the flip side, excessive retardation or complete inhibition of antigen presentation by N-chlorinated plasma proteins could contribute to chronic infection and inflammation.

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MHC class I antigen cross-presentation mediated by PapMV nanoparticles in human antigen-presenting cells is dependent on autophagy.

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