Human CD4+ T cells lyse target cells via Granzyme/Perforin upon circumvention of MHU class II restriction by an antibody-like immunoreceptor
Human CD4+ T cells lyse target cells via Granzyme/Perforin upon circumvention of MHU class II restriction by an antibody-like immunoreceptor
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DOI：
10.4049/jimmunol.177.8.5668
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发表时间：
2006-10-15
影响因子：
4.4
通讯作者：
Abken, Hinrich
中科院分区：
文献类型：
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作者：
Hombach, Andreas;Koehler, Heike;Abken, Hinrich
肿瘤细胞的免疫清除需要CD 8（+）CTL和CD 4（+）Th细胞的密切配合。我们通过表达具有Ab衍生的结合结构域重定向特异性的重组免疫受体来规避CD 4（+）T细胞的MHC II类限制。移植有癌胚抗原（CEA）特异性免疫受体的人CD 4 + T细胞在与CEA（+）靶细胞结合后被激活以增殖并分泌细胞因子。值得注意的是，重定向的CD 4（+）T细胞以高效率介导CEA（+）肿瘤细胞的细胞溶解。重定向的CD 4（+）T细胞的裂解不依赖于通过TNF-α或Fas的死亡受体信号传导，但由穿孔素和颗粒酶介导，因为细胞裂解通过阻断细胞毒性颗粒的释放而不是通过阻断Fas配体或TNF-α来抑制。由Ab衍生的免疫受体以MHC II类非依赖性方式重定向的CD 4（+）T细胞不仅通过CD 4（+）T细胞的帮助，而且通过细胞溶解效应子功能，大大扩展了过继性Ag触发的免疫治疗的能力。由于细胞溶解主要通过颗粒酶/穿孔素介导，因此对死亡受体信号传导具有抗性的靶细胞对工程化CD 4（+）T细胞的细胞溶解攻击变得敏感。
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.