Listeriolysin O-liposome-mediated cytosolic delivery of macromolecule antigen in vivo: Enhancement of antigen-specific cytotoxic T lymphocyte frequency, activity, and tumor protection

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Abstract

Cytotoxic T lymphocytes (CTLs) are primed by peptide antigens that are endogenously processed in the cytosol and presented in the context of major histocompatibility complex I (MHC I) molecules of antigen-presenting cells (APCs). Exogenous soluble protein antigens do not gain efficient entry into the cytosol of APCs, and therefore requires a special cytosolic delivery method. We have developed such a delivery strategy adopting the well-elucidated cytosol-invading listerial endosomal escape mechanism, and report here an efficient delivery of exogenous whole protein antigen into the cytosol in a mouse model. Co-encapsulation of listeriolysin O (LLO) inside liposome (LLO-liposome) was required for delivery of ovalbumin (OVA) into the cytosol of APCs in primary cultures. LLO-liposome-mediated OVA immunization in mice engendered significantly higher OVA-specific CTL activity and increased antigenic peptide-specific CTL precursor (CTLp) frequency as compared to non-LLO-liposome or soluble OVA immunizations. Interferon-γ (IFN-γ) production upon specific stimulation by MHC I-restricted peptide was also significantly stronger by the inclusion of LLO in the liposomes. Rerouting of antigen into the cytosol by LLO-liposomes, however, did not reduce the extent of anti-OVA antibody responses. Moreover, LLO-liposome-antigen vaccination was robust in conferring protection to mice from lethal challenges with antigen-expressing tumor cells. Our study demonstrates a novel delivery system for efficient introduction of exogenous protein into the cytosol in vivo, priming cellular immune responses, which are protective in nature. © 2002 Elsevier Science B.V. All rights reserved.

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Mandal, M., & Lee, K. D. (2002). Listeriolysin O-liposome-mediated cytosolic delivery of macromolecule antigen in vivo: Enhancement of antigen-specific cytotoxic T lymphocyte frequency, activity, and tumor protection. Biochimica et Biophysica Acta - Biomembranes, 1563(1–2), 7–17. https://doi.org/10.1016/S0005-2736(02)00368-1

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