Vaccine-Mediated Inhibition of the Transporter Associated with Antigen Processing Is Insufficient To Induce Major Histocompatibility Complex E-Restricted CD8+ T Cells in Nonhuman Primates

J Virol. 2019 Sep 12;93(19):e00592-19. doi: 10.1128/JVI.00592-19. Print 2019 Oct 1.

Abstract

Major histocompatibility complex E (MHC-E) is a highly conserved nonclassical MHC-Ib molecule that tightly binds peptides derived from leader sequences of classical MHC-Ia molecules for presentation to natural killer cells. However, MHC-E also binds diverse foreign and neoplastic self-peptide antigens for presentation to CD8+ T cells. Although the determinants of MHC-E-restricted T cell priming remain unknown, these cells are induced in humans infected with pathogens containing genes that inhibit the transporter associated with antigen processing (TAP). Indeed, mice vaccinated with TAP-inhibited autologous dendritic cells develop T cells restricted by the murine MHC-E homologue, Qa-1b. Here, we tested whether rhesus macaques (RM) vaccinated with viral constructs expressing a TAP inhibitor would develop insert-specific MHC-E-restricted CD8+ T cells. We generated viral constructs coexpressing SIVmac239 Gag in addition to one of three TAP inhibitors: herpes simplex virus 2 ICP47, bovine herpes virus 1 UL49.5, or rhesus cytomegalovirus Rh185. Each TAP inhibitor reduced surface expression of MHC-Ia molecules but did not reduce surface MHC-E expression. In agreement with modulation of surface MHC-Ia levels, TAP inhibition diminished presentation of MHC-Ia-restricted CD8+ T cell epitopes without impacting presentation of peptide antigen bound by MHC-E. Vaccination of macaques with vectors dually expressing SIVmac239 Gag with ICP47, UL49.5, or Rh185 generated Gag-specific CD8+ T cells classically restricted by MHC-Ia but not MHC-E. These data demonstrate that, in contrast to results in mice, TAP inhibition alone is insufficient for priming of MHC-E-restricted T cell responses in primates and suggest that additional unknown mechanisms govern the induction of CD8+ T cells recognizing MHC-E-bound antigen.IMPORTANCE Due to the near monomorphic nature of MHC-E in the human population and inability of many pathogens to inhibit MHC-E-mediated peptide presentation, MHC-E-restricted T cells have become an attractive vaccine target. However, little is known concerning how these cells are induced. Understanding the underlying mechanisms that induce these T cells would provide a powerful new vaccine strategy to an array of neoplasms and viral and bacterial pathogens. Recent studies have indicated a link between TAP inhibition and induction of MHC-E-restricted T cells. The significance of our research is in demonstrating that TAP inhibition alone does not prime MHC-E-restricted T cell generation and suggests that other, currently unknown mechanisms regulate their induction.

Keywords: MHC-E; RhCMV; T cells; major histocompatibility complex; transporter associated with antigen processing.

Publication types

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

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Enzyme Inhibitors / metabolism
  • Histocompatibility Antigens Class I / metabolism*
  • Macaca mulatta
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • SAIDS Vaccines / administration & dosage
  • SAIDS Vaccines / immunology*
  • Simian Immunodeficiency Virus / immunology*
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / immunology

Substances

  • ATP-Binding Cassette Transporters
  • Enzyme Inhibitors
  • Histocompatibility Antigens Class I
  • Recombinant Proteins
  • SAIDS Vaccines
  • Vaccines, Synthetic
  • transporter associated with antigen processing (TAP)