Co-administration of α-GalCer analog and TLR4 agonist induces robust CD8(+) T-cell responses to PyCS protein and WT-1 antigen and activates memory-like effector NKT cells

Clin Immunol. 2016 Jul;168:6-15. doi: 10.1016/j.clim.2016.04.014. Epub 2016 Apr 27.

Abstract

In the present study, the combined adjuvant effect of 7DW8-5, a potent α-GalCer-analog, and monophosphoryl lipid A (MPLA), a TLR4 agonist, on the induction of vaccine-induced CD8(+) T-cell responses and protective immunity was evaluated. Mice were immunized with peptides corresponding to the CD8(+) T-cell epitopes of a malaria antigen, a circumsporozoite protein of Plasmodium yoelii, and a tumor antigen, a Wilms Tumor antigen-1 (WT-1), together with 7DW8-5 and MPLA, as an adjuvant. These immunization regimens were able to induce higher levels of CD8(+) T-cell responses and, ultimately, enhanced levels of protection against malaria and tumor challenges compared to the levels induced by immunization with peptides mixed with 7DW8-5 or MPLA alone. Co-administration of 7DW8-5 and MPLA induces activation of memory-like effector natural killer T (NKT) cells, i.e. CD44(+)CD62L(-)NKT cells. Our study indicates that 7DW8-5 greatly enhances important synergistic pathways associated to memory immune responses when co-administered with MPLA, thus rendering this combination of adjuvants a novel vaccine adjuvant formulation.

Keywords: Adjuvant; CD1d; Cancer vaccine; Circumsporozoite protein; Glycolipid; Malaria vaccine; Memory-like effector NKT cells; NKT cells; TLR4; WT-1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Drug Synergism
  • Epitopes, T-Lymphocyte / immunology
  • Galactosylceramides / administration & dosage
  • Galactosylceramides / pharmacology*
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunization / methods
  • Immunologic Memory / immunology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lipid A / administration & dosage
  • Lipid A / analogs & derivatives*
  • Lipid A / pharmacology
  • Malaria / immunology
  • Malaria / parasitology
  • Malaria / prevention & control
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Immunological
  • Peptides / immunology
  • Plasmodium yoelii / immunology
  • Plasmodium yoelii / physiology
  • Protective Agents / administration & dosage
  • Protective Agents / pharmacology
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / immunology
  • Toll-Like Receptor 4 / agonists*
  • Toll-Like Receptor 4 / metabolism
  • WT1 Proteins / genetics
  • WT1 Proteins / immunology

Substances

  • 7DW8-5 glycolipid
  • Epitopes, T-Lymphocyte
  • Galactosylceramides
  • HLA-A2 Antigen
  • Lipid A
  • Peptides
  • Protective Agents
  • Protozoan Proteins
  • Toll-Like Receptor 4
  • WT1 Proteins
  • circumsporozoite protein, Protozoan
  • Interferon-gamma
  • monophosphoryl lipid A