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A Brucella spp. Protease Inhibitor Limits Antigen Lysosomal Proteolysis, Increases Cross-Presentation, and Enhances CD8+ T Cell Responses.

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Coria LM, Ibañez AE, Tkach M, Sabbione F, Bruno L, Carabajal MV, Berguer PM, Barrionuevo P, Schillaci R, Trevani AS, Giambartolomei GH, Pasquevich KA, Cassataro J,


Coria LM, Ibañez AE, Tkach M, Sabbione F, Bruno L, Carabajal MV, Berguer PM, Barrionuevo P, Schillaci R, Trevani AS, Giambartolomei GH, Pasquevich KA, Cassataro J, (click to view)

Coria LM, Ibañez AE, Tkach M, Sabbione F, Bruno L, Carabajal MV, Berguer PM, Barrionuevo P, Schillaci R, Trevani AS, Giambartolomei GH, Pasquevich KA, Cassataro J,

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Journal of immunology (Baltimore, Md. : 1950) 2016 4 15() pii

Abstract

In this study, we demonstrate that the unlipidated (U) outer membrane protein (Omp) 19 fromBrucellaspp. is a competitive inhibitor of human cathepsin L. U-Omp19 inhibits lysosome cathepsins and APC-derived microsome activity in vitro and partially inhibits lysosomal cathepsin L activity within live APCs. Codelivery of U-Omp19 with the Ag can reduce intracellular Ag digestion and increases Ag half-life in dendritic cells (DCs). U-Omp19 retains the Ag in Lamp-2(+)compartments after its internalization and promotes a sustained expression of MHC class I/peptide complexes in the cell surface of DCs. Consequently, U-Omp19 enhances Ag cross-presentation by DCs to CD8(+)T cells. U-Omp19 s.c. delivery induces the recruitment of CD11c(+)CD8α(+)DCs and monocytes to lymph nodes whereas it partially limits in vivo Ag proteolysis inside DCs. Accordingly, this protein is able to induce CD8(+)T cell responses in vivo against codelivered Ag. Antitumor responses were elicited after U-Omp19 coadministration, increasing survival of mice in a murine melanoma challenge model. Collectively, these results indicate that a cysteine protease inhibitor from bacterial origin could be a suitable component of vaccine formulations against tumors.

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