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

Abstract

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 a-galactosylceramide (a-GalCer). Following transfer of a transgenic CD8+ T cell population, a single dose of this vaccine induced substantial numbers of intrahepatic 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 proteosomal-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 P. berghei sporozoite challenge after a single dose. Incorporation of a cognate malaria antigen into the vaccine resulted in the generation of large numbers of long-lived liver TRM cells derived from the endogenous T cell population that were capable of providing sterile immunity. 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