Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against rodent malaria

Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against rodent malaria.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1126/sciimmunol.aaz8035
Journal or Publication Title: Science Immunology
Volume: 5
Number: 48
Page Range: eaaz8035
Date: 2020
Divisions: Liver Immunology
Depositing User: General Admin
Identification Number: 10.1126/sciimmunol.aaz8035
ISSN: 2470-9468
Date Deposited: 04 Jan 2021 02:33
Abstract:

Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I–restricted peptide epitope (to stimulate Plasmodium-specific CD8+ T cells) and an adjuvant component, the NKT cell agonist α-galactosylceramide (α-GalCer). A single dose of this vaccine in mice induced substantial numbers of intrahepatic malaria-specific CD8+ T cells expressing canonical markers of liver TRM cells (CD69, CXCR6, and CD101), and these cells could be further increased in number upon vaccine boosting. We show that modifications to the peptide, such as addition of proteasomal-cleavage sequences or epitope-flanking sequences, or the use of alternative conjugation methods to link the peptide to the glycolipid improved liver TRM cell generation and led to the development of a vaccine able to induce sterile protection in C57BL/6 mice against Plasmodium berghei sporozoite challenge after a single dose. Furthermore, this vaccine induced endogenous liver TRM cells that were long-lived (half-life of ~425 days) and were able to maintain >90% sterile protection to day 200. Our findings describe an ideal synthetic vaccine platform for generating large numbers of liver TRM cells for effective control of liver-stage malaria and, potentially, a variety of other hepatotropic infections.

Creators:
Creators
Email
Holz, Lauren E.
UNSPECIFIED
Chua, Yu Cheng
UNSPECIFIED
de Menezes, Maria N.
UNSPECIFIED
Anderson, Regan J.
UNSPECIFIED
Draper, Sarah L.
UNSPECIFIED
Compton, Benjamin J.
UNSPECIFIED
Chan, Susanna T. S.
UNSPECIFIED
Mathew, Juby
UNSPECIFIED
Li, Jasmine
UNSPECIFIED
Kedzierski, Lukasz
UNSPECIFIED
Wang, Zhongfang
UNSPECIFIED
Beattie, Lynette
UNSPECIFIED
Enders, Matthias H.
UNSPECIFIED
Ghilas, Sonia
UNSPECIFIED
May, Rose
UNSPECIFIED
Steiner, Thiago M.
UNSPECIFIED
Lange, Joshua
UNSPECIFIED
Fernandez-Ruiz, Daniel
UNSPECIFIED
Valencia-Hernandez, Ana Maria
UNSPECIFIED
Osmond, Taryn L.
UNSPECIFIED
Farrand, Kathryn J.
UNSPECIFIED
Seneviratna, Rebecca
UNSPECIFIED
Almeida, Catarina F.
UNSPECIFIED
Tullett, Kirsteen M.
UNSPECIFIED
Bertolino, Patrick
UNSPECIFIED
Bowen, David G.
UNSPECIFIED
Cozijnsen, Anton
UNSPECIFIED
Mollard, Vanessa
UNSPECIFIED
McFadden, Geoffrey I.
UNSPECIFIED
Caminschi, Irina
UNSPECIFIED
Lahoud, Mireille H.
UNSPECIFIED
Kedzierska, Katherine
UNSPECIFIED
Turner, Stephen J.
UNSPECIFIED
Godfrey, Dale I.
UNSPECIFIED
Hermans, Ian F.
UNSPECIFIED
Painter, Gavin F.
UNSPECIFIED
Heath, William R.
UNSPECIFIED
Last Modified: 04 Jan 2021 02:33
URI: https://eprints.centenary.org.au/id/eprint/775

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