Hombach Andreas, Köhler Heike, Rappl Gunter, Abken Hinrich
Klinik I für Innere Medizin, Labor Tumorgenetik, and Zentrum für Molekulare Medizin Köln, Universität zu Köln, Köln, Germany.
J Immunol. 2006 Oct 15;177(8):5668-75. doi: 10.4049/jimmunol.177.8.5668.
Immune elimination of tumor cells requires the close cooperation between CD8+ CTL and CD4+ Th cells. We circumvent MHC class II-restriction of CD4+ T cells by expression of a recombinant immunoreceptor with an Ab-derived binding domain redirecting specificity. Human CD4+ T cells grafted with an immunoreceptor specific for carcinoembryonic Ag (CEA) are activated to proliferate and secrete cytokines upon binding to CEA+ target cells. Notably, redirected CD4+ T cells mediate cytolysis of CEA+ tumor cells with high efficiencies. Lysis by redirected CD4+ T cells is independent of death receptor signaling via TNF-alpha or Fas, but mediated by perforin and granzyme because cytolysis is inhibited by blocking the release of cytotoxic granules, but not by blocking of Fas ligand or TNF-alpha. CD4+ T cells redirected by Ab-derived immunoreceptors in a MHC class II-independent fashion substantially extend the power of an adoptive, Ag-triggered immunotherapy not only by CD4+ T cell help, but also by cytolytic effector functions. Because cytolysis is predominantly mediated via granzyme/perforin, target cells that are resistant to death receptor signaling become sensitive to a cytolytic attack by engineered CD4+ T cells.
肿瘤细胞的免疫清除需要CD8⁺细胞毒性T淋巴细胞（CTL）和CD4⁺辅助性T细胞（Th细胞）密切合作。我们通过表达一种带有源自抗体的结合结构域以重定向特异性的重组免疫受体，规避了CD4⁺T细胞的MHC II类限制。移植了对癌胚抗原（CEA）具有特异性的免疫受体的人CD4⁺T细胞，在与CEA⁺靶细胞结合后被激活，从而增殖并分泌细胞因子。值得注意的是，重定向的CD4⁺T细胞能高效介导CEA⁺肿瘤细胞的细胞溶解。重定向的CD4⁺T细胞介导的细胞溶解不依赖于通过肿瘤坏死因子-α（TNF-α）或Fas的死亡受体信号传导，而是由穿孔素和颗粒酶介导，因为细胞溶解可通过阻断细胞毒性颗粒的释放而受到抑制，但不能通过阻断Fas配体或TNF-α来抑制。以不依赖MHC II类的方式由源自抗体的免疫受体重定向的CD4⁺T细胞，不仅通过CD4⁺T细胞的辅助作用，还通过细胞溶解效应功能，极大地扩展了过继性、抗原触发的免疫疗法的效能。由于细胞溶解主要通过颗粒酶/穿孔素介导，对死亡受体信号传导有抗性的靶细胞对工程化CD4⁺T细胞的细胞溶解攻击变得敏感。
