生物
细胞毒性T细胞
抗原
分子生物学
主要组织相容性复合体
T细胞受体
CTL公司*
链霉菌
T细胞
抗原提呈细胞
CD28
抗体
CD8型
免疫学
免疫系统
体外
生物化学
作者
Yoko Inaguma,Yasushi Akahori,Yuko Murayama,Keiko Shiraishi,Sachiko Tsuzuki-Iba,Akira Endoh,Juri Tsujikawa,Ayako Demachi-Okamura,K Hiramatsu,Hiroh Saji,Yukiya Yamamoto,Naoki Yamamoto,Yasuharu Nishimura,Toshitada Takahashi,Kiyotaka Kuzushima,Nobuhiko Emi,Yoshiki Akatsuka
出处
期刊:Gene Therapy
[Springer Nature]
日期:2014-04-03
卷期号:21 (6): 575-584
被引量:37
摘要
The genetic transfer of T-cell receptors (TCRs) directed toward target antigens into T lymphocytes has been used to generate antitumor T cells efficiently without the need for the in vitro induction and expansion of T cells with cognate specificity. Alternatively, T cells have been gene-modified with a TCR-like antibody or chimeric antigen receptor (CAR). We show that immunization of HLA-A2 transgenic mice with tetramerized recombinant HLA-A2 incorporating HA-1 H minor histocompatibility antigen (mHag) peptides and β2-microglobulin (HA-1 H/HLA-A2) generate highly specific antibodies. One single-chain variable region moiety (scFv) antibody, #131, demonstrated high affinity (KD=14.9 nM) for the HA-1 H/HLA-A2 complex. Primary human T cells transduced with #131 scFV coupled to CD28 transmembrane and CD3ζ domains were stained with HA-1 H/HLA-A2 tetramers slightly more intensely than a cytotoxic T lymphocyte (CTL) clone specific for endogenously HLA-A2- and HA-1 H-positive cells. Although #131 scFv CAR-T cells required >100-fold higher antigen density to exert cytotoxicity compared with the cognate CTL clone, they could produce inflammatory cytokines against cells expressing HLA-A2 and HA-1 H transgenes. These data implicate that T cells with high-affinity antigen receptors reduce the ability to lyse targets with low-density peptide/MHC complexes (~100 per cell), while they could respond at cytokine production level.
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