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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 K; Park, Byung S; Asokan, Aravind; Früh, Klaus; Hansen, Scott G; Picker, Louis J; Sacha, Jonah B.
  • Abdulhaqq SA; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Wu H; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Schell JB; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Hammond KB; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Reed JS; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Legasse AW; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Axthelm MK; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Park BS; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Asokan A; Department of Surgery, Duke University, Durham, North Carolina, USA.
  • Früh K; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Hansen SG; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Picker LJ; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
  • Sacha JB; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA sacha@ohsu.edu.
J Virol ; 93(19)2019 10 01.
Article en En | MEDLINE | ID: mdl-31315990
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Antígenos de Histocompatibilidad Clase I / Virus de la Inmunodeficiencia de los Simios / Vacunas contra el SIDAS / Linfocitos T CD8-positivos / Transportadoras de Casetes de Unión a ATP Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Año: 2019 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Antígenos de Histocompatibilidad Clase I / Virus de la Inmunodeficiencia de los Simios / Vacunas contra el SIDAS / Linfocitos T CD8-positivos / Transportadoras de Casetes de Unión a ATP Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Año: 2019 Tipo del documento: Article