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
| Autor: | Shaheed A. Abdulhaqq, Jonah B. Sacha, Scott G. Hansen, Katherine B. Hammond, Jason S. Reed, Klaus Früh, Helen L. Wu, Michael K. Axthelm, Byung Park, Louis J. Picker, Alfred W. Legasse, Aravind Asokan, John B. Schell |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
T cell
Immunology Population Priming (immunology) chemical and pharmacologic phenomena Biology CD8-Positive T-Lymphocytes Major histocompatibility complex Microbiology 03 medical and health sciences 0302 clinical medicine Antigen Virology Vaccines and Antiviral Agents medicine Cytotoxic T cell Animals Enzyme Inhibitors education 030304 developmental biology 0303 health sciences education.field_of_study Vaccines Synthetic Histocompatibility Antigens Class I SAIDS Vaccines Transporter associated with antigen processing Macaca mulatta Recombinant Proteins Cell biology medicine.anatomical_structure Insect Science biology.protein ATP-Binding Cassette Transporters Simian Immunodeficiency Virus CD8 030215 immunology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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