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

Shaheed A. Abdulhaqq, Helen Wu, John B. Schell, Katherine B. Hammond, Jason S. Reed, Alfred W. Legasse, Michael Axthelm, Byung Park, Aravind Asokan, Klaus Frueh, Scott Hansen, Louis Picker, Jonah Sacha

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJournal of virology
Volume93
Issue number19
DOIs
StatePublished - Oct 1 2019

Fingerprint

Antigen Presentation
major histocompatibility complex
Major Histocompatibility Complex
Primates
transporters
Vaccines
T-lymphocytes
vaccines
antigens
T-Lymphocytes
peptides
pathogens
mice
Human herpesvirus 2
Cytomegalovirus
antigen presentation
Peptides
T-Lymphocyte Epitopes
Human Herpesvirus 2
Autoantigens

Keywords

  • major histocompatibility complex
  • MHC-E
  • RhCMV
  • T cells
  • transporter associated with antigen processing

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

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. / Abdulhaqq, Shaheed A.; Wu, Helen; Schell, John B.; Hammond, Katherine B.; Reed, Jason S.; Legasse, Alfred W.; Axthelm, Michael; Park, Byung; Asokan, Aravind; Frueh, Klaus; Hansen, Scott; Picker, Louis; Sacha, Jonah.

In: Journal of virology, Vol. 93, No. 19, 01.10.2019.

Research output: Contribution to journalArticle

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AU - Wu, Helen

AU - Schell, John B.

AU - Hammond, Katherine B.

AU - Reed, Jason S.

AU - Legasse, Alfred W.

AU - Axthelm, Michael

AU - Park, Byung

AU - Asokan, Aravind

AU - Frueh, Klaus

AU - Hansen, Scott

AU - Picker, Louis

AU - Sacha, Jonah

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