CRYSTAL STRUCTURES OF TCR AND MHC AND CD4 COMPLEX

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 虽然大多数癌症免疫疗法集中于引发特异性CD 8+细胞毒性T淋巴细胞杀伤肿瘤细胞，但越来越多的证据表明，刺激抗肿瘤CD 4 + T细胞可能是高效治疗所必需的。现在已经鉴定了几种特异性激活这种CD 4+辅助T淋巴细胞的MHC II类限制性肿瘤抗原，包括来自黑色素瘤肿瘤的一种，其由糖酵解酶磷酸丙糖异构酶（TPI）中的单碱基对突变引起。该突变导致抗原表位内的苏氨酸残基转化为异亮氨酸，伴随着对CD 4+肿瘤浸润淋巴细胞系（TIL 1558）的刺激增加大于5个对数倍。来自寡克隆TIL 1558系的不同TCR，包括E8和G4，已经显示出优先识别由HLA-DR 1呈递的突变TPI肽的能力。 为了理解增强的CD 4 + T细胞对突变肽识别的结构基础，我们获得了与HLA-DR 1呈递的野生型和突变TPI抗原结合的TCR E8晶体。这些E8/TPI/HLA-DR 1复合物结构代表了能够刺激CD 4 + T细胞的肿瘤抗原的首次结构分析。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. While most cancer immunotherapies have focused on eliciting specific CD8+ cytotoxic T lymphocyte killing of tumor cells, a mounting body of evidence suggests that stimulation of anti-tumor CD4+ T cell may be required for highly effective therapy. Several MHC class II-restricted tumor antigens that specifically activate such CD4+ helper T lymphocytes have now been identified, including one from a melanoma tumor that is caused by a single base-pair mutation in the glycolytic enzyme triosephosphate isomerase (TPI). This mutation results in the conversion of a threonine residue to isoleucine within the antigenic epitope, concomitant with a greater than five log-fold increase in stimulation of a CD4+ tumor-infiltrating lymphocyte line (TIL 1558). Different TCRs from the oligoclonal TIL 1558 line, including E8 and G4, have shown the ability to preferentially recognize the mutant TPI peptide presented by HLA-DR1. In order to understand the structural basis for enhanced CD4+ T cell recognition of the mutant peptide, we have obtained the crystals of TCR E8 bound to both wild-type and mutant TPI antigens presented by HLA-DR1. These E8/TPI/HLA-DR1 complex structures represent the first structural analysis of tumor antigens capable of stimulating CD4+ T cells.