Crisscross CTL induction by SYT-SSX junction peptide and its HLA-A*2402 anchor substitute.

نویسندگان

  • Kazunori Ida
  • Satoshi Kawaguchi
  • Yuriko Sato
  • Tomohide Tsukahara
  • Yuki Nabeta
  • Hiroeki Sahara
  • Hideyuki Ikeda
  • Toshihiko Torigoe
  • Shingo Ichimiya
  • Kenjiro Kamiguchi
  • Takuro Wada
  • Satoshi Nagoya
  • Hiroaki Hiraga
  • Akira Kawai
  • Takeshi Ishii
  • Nobuhito Araki
  • Akira Myoui
  • Seiichi Matsumoto
  • Toshifumi Ozaki
  • Hideki Yoshikawa
  • Toshihiko Yamashita
  • Noriyuki Sato
چکیده

To investigate the effects of anchor substitutions in SYT-SSX junction peptide, an HLA-A24 anchor residue (position 9) of the SYT-SSX B peptide (GYDQIMPKK) was substituted to more favorable residues according to the HLA-A24-binding motif. Among four substitutes constructed, a substitute with isoleucine (termed K9I peptide) most apparently enhanced the affinity for HLA-A24 molecule. Subsequent in vitro CTL induction analysis using PBMCs of 15 HLA-A24(+) synovial sarcoma patients revealed that the original B peptide allowed to induce synovial sarcoma-specific CTLs from 7 patients (47%), whereas such CTLs were inducible from 12 patients (80%) with K9I peptide. Moreover, the extent of cytotoxicity against HLA-A24(+) synovial sarcoma cell lines was higher in K9I peptide-induced CTLs than B peptide-induced CTLs. Influence of anchor substitution on peptide/TCR interaction was evaluated by cytotoxicity assays against autologous cells and tetramer analysis. CTLs induced from a synovial sarcoma patient using K9I peptide did not lyse autologous PHA blasts or EBV-infected B cells. In vitro stimulations of PBMCs from 5 HLA-A24(+) synovial sarcoma patients with K9I peptide increased the frequency of T cells reacting with both HLA-A24/K9I peptide tetramer and HLA-A24/B peptide tetramer. In contrast, the frequency of T cells reacting with HLA/HIV-derived peptide tetramer remained low. These findings support the validity in design of anchor residue substitution in SYT-SSX fusion gene-derived peptide, and provide a potential clue to the current stagnation in vaccination trials of fusion gene-derived natural junction peptides.

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عنوان ژورنال:
  • Journal of immunology

دوره 173 2  شماره 

صفحات  -

تاریخ انتشار 2004