Department of Pathology, Committee on Immunology, The University of Chicago, Chicago, Illinois 60637-5420, USA.
Mol Ther. 2012 Mar;20(3):652-60. doi: 10.1038/mt.2011.286. Epub 2012 Jan 10.
Most T cells have T cell receptors (TCR) of micromolar affinity for peptide-major histocompatibility complex (MHC) ligands, but genetic engineering can generate TCRs of nanomolar affinity. The affinity of the TCR used, m33, for its cognate non-self peptide-MHC-I complex (SIYRYYGL-K(b)) is 1,000-fold higher than of the wild-type TCR 2C. The affinity of m33 for the self-peptide dEV-8 on K(b) is only twofold higher. Mouse CD8(+) T cells transduced with an m33-encoding retrovirus showed binding of SIY-K(b) and potent function in vitro, but in vivo these T cells disappeared within hours after transfer into syngeneic hosts without causing graft-versus-host disease (GVHD). Accordingly, in cases where such CD8-dependent self-reactivity might occur in human adoptive T cell therapies, our results show that a peripheral T-cell deletion mechanism could operate to avoid reactions with the host. In contrast to CD8(+) T cells, we show that CD4(+) T cells expressing m33 survived for months in vivo. Furthermore, the m33-transduced CD4(+) T cells were able to mediate antigen-specific rejection of 6-day-old tumors. Together, we show that CD8(+) T cell expressing a MHC class I-restricted high-affinity TCR were rapidly deleted whereas CD4(+) T cells expressing the same TCR survived and provided function while being directed against a class I-restricted antigen.
大多数 T 细胞的 T 细胞受体 (TCR) 对肽-主要组织相容性复合体 (MHC) 配体的亲和力为微摩尔级，但基因工程可以产生纳摩尔级亲和力的 TCR。所使用的 TCR（m33）与其同源非自身肽-MHC-I 复合物（SIYRYYGL-K(b)）的亲和力比野生型 TCR 2C 高 1000 倍。m33 与 K(b) 上自身肽 dEV-8 的亲和力仅高出两倍。用编码 m33 的逆转录病毒转导的小鼠 CD8(+) T 细胞显示出对 SIY-K(b)的结合和体外强大的功能，但在体内，这些 T 细胞在转移到同基因宿主后数小时内消失，而不会引起移植物抗宿主病 (GVHD)。因此，在人类过继性 T 细胞治疗中可能发生这种 CD8 依赖性自身反应的情况下，我们的结果表明，外周 T 细胞删除机制可能会发挥作用，以避免与宿主发生反应。与 CD8(+) T 细胞相反，我们表明表达 m33 的 CD4(+) T 细胞在体内存活了数月。此外，转导 m33 的 CD4(+) T 细胞能够介导针对 6 天龄肿瘤的抗原特异性排斥。总之，我们表明表达 MHC Ⅰ类限制性高亲和力 TCR 的 CD8(+) T 细胞迅速被删除，而表达相同 TCR 的 CD4(+) T 细胞存活并提供功能，同时针对 I 类限制性抗原。
