Institute for Virology, University of Duisburg-Essen, Virchowstr 179, 45147, Essen, Germany.
Cancer Immunol Immunother. 2013 Feb;62(2):257-71. doi: 10.1007/s00262-012-1329-y. Epub 2012 Aug 14.
The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.
肿瘤特异性细胞毒性 CD8(+) T 细胞在肿瘤的免疫控制中起着重要作用，但效应 CD4(+) T 细胞的作用却知之甚少。在目前的研究中，我们使用了一种源自 C57BL/6 小鼠的鼠逆转录病毒诱导的肿瘤细胞系 FBL-3 细胞作为模型，研究肿瘤形成过程中免疫控制和逃逸的基本机制。本研究表明，肿瘤特异性 CD4(+) T 细胞能够抵抗病毒诱导的肿瘤细胞。我们在这里表明，在肿瘤生长的早期阶段，会扩增产生细胞因子和细胞毒性分子颗粒酶 B (GzmB)的肿瘤特异性 CD4(+) T 细胞。重要的是，我们证明了在 FBL-3 荷瘤 DEREG 转基因小鼠中体内耗竭调节性 T 细胞 (Tregs) 和 CD8(+) T 细胞会增加 CD4(+) T 细胞中 IL-2 和 GzmB 的产生，并增强 FV 特异性 CD4(+) T 细胞效应和细胞毒性反应，导致肿瘤完全消退。因此，肿瘤反应性 CD4(+) T 细胞获得的排斥肿瘤的能力在很大程度上取决于 Tregs 的直接抑制活性。我们认为，可以诱导细胞毒性 CD4(+) T 细胞免疫反应来增强对致癌病毒相关肿瘤的抵抗力。
