Target epitope in the Tax protein of human T-cell leukemia virus type I recognized by class I major histocompatibility complex-restricted cytotoxic T cells

Abstract

A transacting regulatory gene product p4O' (Tax) of human T-cell leukemia virus type I (HTLV-I) is one of the main target antigens recognized by cytotoxic T lymphocytes (CTL) specific for HTLV-I. A CTL epitope within the Tax protein was identified in this report. HTLV-I-specific CD8+ CTL lines established from two HTLV-I carriers with HTLV-I-associated myelopathy or Sjogren syndrome were previously demonstrated to kill predominantly the target cells expressing HTLV-I Tax. The CTL from two patients showed significant levels of cytotoxicity to autologous target cells pulsed with a synthetic peptide of 24 amino acids corresponding to the amino-terminal sequences of the Tax protein. Allogeneic target cells were also sensitized for CTL by this peptide when the target cells have HLA-A2. Tax-specific cytotoxicity, detected as cytolysis of the target cells infected with vaccinia virus-HTLV-I recombinant expressing Tax protein, was almost completely inhibited by competitor cells pulsed with the synthetic peptide. This indicates that a major CTL epitope is present in this peptide. Further analysis using shorter peptides revealed that the core sequence of the CTL epitope was LLFGYPVYV at positions 11 through 19. This sequence can be aligned with the HLA-A2-specific motifs reported recently.

Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity

“…Consistent with the previous data, 5 RMA-H74L cells were lysed by influenza A matrix peptide (FMP 58-66 )-specific CTLs at much lower peptide concentrations than RMA-HHD cells (Figure 1c). Similar results were obtained with different HLA-A*02:01-restricted peptides derived from human papillomavirus (HPV)-E6 (HPV-E6 [29][30][31][32][33][34][35][36][37][38] ), human T-lymphotropic virus (HTLV)-tax (HTLV-tax [11][12][13][14][15][16][17][18][19] ) and human immunodeficiency virus (HIV)-pol (HIV-pol 476-484 ) (Figure 1c), indicating that this phenomenon was not peptide-specific as described in the previous studies. 18 The peptide-binding studies were conducted using the transporter associated antigen processing-2 (TAP-2) deficient cell line, RMA-S 19 expressing HHD (RMA-S-HHD) or HHD-H74L (RMA-S-H74L).…”

“…HLA-A*02:01-restricted epitopes used were as follows: FMP 58-66 (sequence: GILGFVFTL), 31 HPV-E6 [29][30][31][32][33][34][35][36][37][38] (sequence: TIHDIILECV), 32 HTLV-tax [11][12][13][14][15][16][17][18][19] (sequence: LLFGYPVYV), 33 and HIV-pol 476-484 (sequence: ILKEPVHGV). 34 Synthetic peptides corresponding to the above epitopes were synthesized by Operon Biotechnologies (Tokyo, Japan).…”

“…(c) Enhanced cytotoxic T lymphocyte (CTL) recognition of HHD-H74L-expressing targets. CTL lines were examined for killing activities against RMA, RMA-HHD and RMA-H74L in the presence of a peptide (FMP 58-66 , HPV-E6 [29][30][31][32][33][34][35][36][37][38] , HTLV-tax [11][12][13][14][15][16][17][18][19] or HIV-pol [476][477][478][479][480][481][482][483][484] ) by 51 Cr-release assays. Data are shown as the mean ± SD of triplicate wells.…”

Presentation of human T cell leukemia virus type 1 (HTLV-1) Tax protein by dendritic cells: the underlying mechanism of HTLV-1-associated neuroinflammatory disease

“…In patients with HAM/TSP, a high frequency of HLA-A2-restricted, Taxspecific CTLs correlates positively with virus burden and Tax expression, indicating the existence of continuous antigen presentation [18,19,21,41]. Therefore, the main focus of this study was to determine the maximal route of Tax-specific CTL activation targeting epitope 11-19, as the affinity of this epitope for HLA-A2 was shown to be unusually high [24], and the Tax 11-19specific response is immunodominant frequently in patients with HAM/TSP [16,[25][26][27]. Using in vitro and in vivo priming assays, we demonstrated that DCs could drive an efficient Tax-specific CTL response in naïve PBLs from the normal donor as well as in HHD II mice.…”

Expression of the target antigen for cytotoxic T lymphocytes on adult T‐cell‐leukemia cells

“…Cytotoxic T lymphocytes (CTL) specific for HTLV-I were induccd from peripheral-blood mononuclear cells (PBMC) of a HAM patient by repeated in vitro stimulation with autologous HTLV-I-infected T cells, as described (Kannagi et al, 1991). These CTL predominantly recognize HTLV-I tax, and the main CTL epitope in the tax molecule is a nonapeptide LLFGYPVYV at positions 11 through 19, which is presented with HLA-A2 molecule (Kannagi et al, 1992). These CTL were maintained in a medium containing TL-2 (Shionogi, Osaka, Japan), with periodic in vitro stimulation with HTLV-Iinfected cells.…”