Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
J Immunol. 2011 Sep 1;187(5):2453-63. doi: 10.4049/jimmunol.1101268. Epub 2011 Jul 27.
T cells engineered to express TCRs specific for tumor Ags can drive cancer regression. The first TCRs used in cancer gene therapy, DMF4 and DMF5, recognize two structurally distinct peptide epitopes of the melanoma-associated MART-1/Melan-A protein, both presented by the class I MHC protein HLA-A*0201. To help understand the mechanisms of TCR cross-reactivity and provide a foundation for the further development of immunotherapy, we determined the crystallographic structures of DMF4 and DMF5 in complex with both of the MART-1/Melan-A epitopes. The two TCRs use different mechanisms to accommodate the two ligands. Although DMF4 binds the two with a different orientation, altering its position over the peptide/MHC, DMF5 binds them both identically. The simpler mode of cross-reactivity by DMF5 is associated with higher affinity toward both ligands, consistent with the superior functional avidity of DMF5. More generally, the observation of two diverging mechanisms of cross-reactivity with the same Ags and the finding that TCR-binding orientation can be determined by peptide alone extend our understanding of the mechanisms underlying TCR cross-reactivity.
经基因工程改造表达 TCR 的 T 细胞可驱动肿瘤消退。在癌症基因治疗中首次使用的 DMF4 和 DMF5 识别两种结构上不同的黑色素瘤相关 MART-1/Melan-A 蛋白的肽表位，均由 I 类 MHC 蛋白 HLA-A*0201 呈递。为了帮助理解 TCR 交叉反应的机制，并为进一步开发免疫疗法提供基础，我们确定了 DMF4 和 DMF5 与两种 MART-1/Melan-A 表位结合的晶体结构。这两种 TCR 采用不同的机制来适应两种配体。尽管 DMF4 以不同的取向与两种配体结合，改变其在肽/MHC 上的位置，但 DMF5 以相同的方式与它们结合。DMF5 更简单的交叉反应模式与对两种配体的更高亲和力相关，这与 DMF5 的优越功能亲和力一致。更普遍的是，观察到与相同抗原的两种不同的交叉反应机制，并且发现 TCR 结合取向可以仅由肽决定，这扩展了我们对 TCR 交叉反应机制的理解。
