Dataset Information

N-Terminal Fatty Acids of NEFMUT Are Required for the CD8+ T-Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles.

ABSTRACT: We recently described a cytotoxic CD8+ T lymphocyte (CTL) vaccine platform based on the intramuscular (i.m.) injection of DNA eukaryotic vectors expressing antigens of interest fused at the C-terminus of HIV-1 Nefmut, i.e., a functionally defective mutant that is incorporated at quite high levels into exosomes/extracellular vesicles (EVs). This system has been proven to elicit strong CTL immunity against a plethora of both viral and tumor antigens, as well as inhibit both transplantable and orthotopic tumors in mice. However, a number of open issues remain regarding the underlying mechanism. Here we provide evidence that hindering the uploading into EVs of Nefmut-derived products by removing the Nefmut N-terminal fatty acids leads to a dramatic reduction of the downstream antigen-specific CD8+ T-cell activation after i.m. injection of DNA vectors in mice. This result formally demonstrates that the generation of engineered EVs is part of the mechanism underlying the in vivo induced CD8+ T-cell immunogenicity. Gaining new insights on the EV-based vaccine platform can be relevant in view of its possible translation into the clinic to counteract both chronic and acute infections as well as tumors.

SUBMITTER: Chiozzini C

PROVIDER: S-EPMC7350016 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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N-Terminal Fatty Acids of NEFMUT Are Required for the CD8+ T-Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles.

Chiozzini Chiara C Manfredi Francesco F Arenaccio Claudia C Ferrantelli Flavia F Leone Patrizia P Federico Maurizio M

Vaccines 20200522 2

We recently described a cytotoxic CD8+ T lymphocyte (CTL) vaccine platform based on the intramuscular (i.m.) injection of DNA eukaryotic vectors expressing antigens of interest fused at the C-terminus of HIV-1 Nefmut, i.e., a functionally defective mutant that is incorporated at quite high levels into exosomes/extracellular vesicles (EVs). This system has been proven to elicit strong CTL immunity against a plethora of both viral and tumor antigens, as well as inhibit both t ...[more]

PMID: 32456079

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Project description:Psoriasis is an inflammatory skin disease mainly associated with an epidermal disorder. However, the involvement of the dermal extracellular matrix (ECM) composition in psoriasis is still poorly understood. This study aimed to investigate the expression of ECM components in psoriatic skin substitutes (PS-) compared with healthy skin substitutes (HS-), as well as the effect of an n-3 polyunsaturated fatty acid, namely α-linolenic acid (ALA), on the psoriatic dermal compartment (PSALA+). Liquid chromatography tandem mass spectrometry analyses revealed that the lipidome of PS- contained higher amounts of n-6 derived prostaglandins (PGE2) and lipoxygenase products (9-HODE and 15-HETE). ALA supplementation increased the levels of PGE3, 13-HOTrE, 15-HEPE, and 18-HEPE, and decreased the levels of PGE2, 15-HETE, and 9-HOPE compared with PS-, indicating that ALA modulates the dermal lipidome of psoriatic skin substitutes. Gene expression profiling showed that several genes encoding for different ECM proteins were overexpressed in PS- compared with HS-, namely COL1A1 (4.2-fold), COL1A2 (3-fold), COL3A1 (4.4-fold), COL4A1 (2.3-fold), COL4A2 (6.3-fold), COL5A1 (3.3-fold), COL5A2 (5.2-fold), and COL5A3 (4.6-fold). Moreover, the expression of collagen IV (Col IV), collagen VII (Col VII), and laminin was found to be increased in PS- compared with HS-, and to be restored with ALA (PSALA+) according to immunofluorescence staining, while only the collagen I to collagen III ratio was altered according to dot blot analyses. Linear regression analysis revealed several positive correlations, including Col III with 14-HDHA levels, fibronectin with 12-HETE and 15-HETE levels, the dermo-epidermal junction Col IV with PGF2α, 9-HODE, and 13-HODE levels, and laminin with levels of PGF2α, 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE. These results suggest that the ECM plays an underestimated role in the pathogenesis of psoriasis and that ALA supplementation can regulate the ECM composition.

Dataset Information

N-Terminal Fatty Acids of NEFMUT Are Required for the CD8+ T-Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles.

Publications

N-Terminal Fatty Acids of NEF<sup>MUT</sup> Are Required for the CD8<sup>+</sup> T-Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles.

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