Kuball Jürgen, Schmitz Frank W, Voss Ralf-Holger, Ferreira Edite Antunes, Engel Renate, Guillaume Philippe, Strand Susanne, Romero Pedro, Huber Christoph, Sherman Linda A, Theobald Matthias
Department of Hematology and Oncology, Johannes Gutenberg University, 55101 Mainz, Germany.
Immunity. 2005 Jan;22(1):117-29. doi: 10.1016/j.immuni.2004.12.005.
Efficient immune attack of malignant disease requires the concerted action of both CD8+ CTL and CD4+ Th cells. We used human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic mice, in which the mouse CD8 molecule cannot efficiently interact with the alpha3 domain of A2.1, to generate a high-affinity, CD8-independent T cell receptor (TCR) specific for a commonly expressed, tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the human p53 tumor suppressor protein. Retroviral expression of this CD8-independent, p53-specific TCR into human T cells imparted the CD8+ T lymphocytes with broad tumor-specific CTL activity and turned CD4+ T cells into potent tumor-reactive, p53A2.1-specific Th cells. Both T cell subsets were cooperative and interacted synergistically with dendritic cell intermediates and tumor targets. The intentional redirection of both CD4+ Th cells and CD8+ CTL by the same high-affinity, CD8-independent, tumor-specific TCR could provide the basis for novel broad-spectrum cancer immunotherapeutics.
对恶性疾病进行有效的免疫攻击需要CD8 + CTL和CD4 + Th细胞的协同作用。我们使用了人类白细胞抗原（HLA）-A*0201（A2.1）转基因小鼠，在这种小鼠中，小鼠CD8分子不能有效地与A2.1的α3结构域相互作用，以产生对源自人类p53肿瘤抑制蛋白的常见表达的肿瘤相关细胞毒性T淋巴细胞（CTL）表位具有高亲和力、不依赖CD8的T细胞受体（TCR）。将这种不依赖CD8、p53特异性的TCR逆转录病毒表达到人T细胞中，赋予CD8 + T淋巴细胞广泛的肿瘤特异性CTL活性，并将CD4 + T细胞转变为有效的肿瘤反应性、p53A2.1特异性Th细胞。这两个T细胞亚群相互协作，并与树突状细胞中间体和肿瘤靶标协同相互作用。通过相同的高亲和力、不依赖CD8的肿瘤特异性TCR对CD4 + Th细胞和CD8 + CTL进行定向重编程，可为新型广谱癌症免疫疗法提供基础。
