Presentation of a new H-2D(k)-restricted epitope in the Tax protein of human T-lymphotropic virus type I is enhanced by the proteasome inhibitor lactacystin.
Tax, the trans-activator of human T-lymphotropic virus type I (HTLV-I), is the dominant target antigen for cytotoxic T lymphocytes (CTLs) in the majority of infected individuals, although the reason for this immunodominance is not clear. Tax has been shown to associate physically with the proteasome, a protease that is responsible for the generation of the majority of major histocompatibility complex (MHC) class I ligands recognized by CTLs. This association could lead to the preferential targeting of Tax to the MHC class I pathway and account for its high immunogenicity. Here, the CTL response to Tax was investigated in mice by priming with a Tax expression vector and boosting with a Tax recombinant vaccinia virus (modified vaccinia virus Ankara strain). This approach led to the identification of a new H-2D(k)-restricted epitope in Tax, amino acid residues 38-46, sequence ARLHRHALL. Surprisingly, presentation of this epitope was found to be enhanced by the proteasome inhibitor lactacystin, although Tax was shown to associate with proteasomes in murine cells. The difficulties encountered in generating Tax-specific CTL responses and the results of enzyme-linked immunospot (ELISpot) analysis suggested that Tax is only poorly immunogenic for CTLs in mice. Therefore, the immunodominance of Tax in human CTL responses to HTLV-I is probably not due to an intrinsic property of the protein itself, such as an association with the proteasome, but instead may result from the fact that Tax is the predominant protein synthesized early after infection.
Lomas
Mehnaaz
M
Department of Immunology, Imperial College School of Medicine (St Mary's Campus), Norfolk Place, London W2 1PG, UK1.
Hanon
Emmanuel
E
Department of Immunology, Imperial College School of Medicine (St Mary's Campus), Norfolk Place, London W2 1PG, UK1.
Tanaka
Yuetsu
Y
Department of Infectious Disease and Immunology, Okinawa-Asia Research Centre of Medical Science, Faculty of Medicine, University of the Ryukyus, Uehara-cho 207, Nishihara, Okinawa 903-0215, Japan2.
Bangham
Charles R M
CRM
Department of Immunology, Imperial College School of Medicine (St Mary's Campus), Norfolk Place, London W2 1PG, UK1.
Gould
Keith G
KG
Department of Immunology, Imperial College School of Medicine (St Mary's Campus), Norfolk Place, London W2 1PG, UK1.
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D002460:Cell Line; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D005260:Female; D016356:Gene Products, tax / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors / Q000235:genetics; D006183:H-2 Antigens / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
D018984:Epitopes, T-Lymphocyte; D016356:Gene Products, tax; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D009097:Multienzyme Complexes; D010446:Peptide Fragments; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine