Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injuries, Southwest Hospital, Chongqing Key Laboratory for Disease Proteomics, Third Military Medical University, Chongqing 400038, China.
Cell Res. 2012 Dec;22(12):1696-706. doi: 10.1038/cr.2012.128. Epub 2012 Sep 4.
The regulatory activities of mouse CD4(+)Foxp3(+) T cells on various immune cells, including NK cells, have been well documented. Under some conditions, conventional CD4(+)Foxp3(-) T cells in the periphery are able to acquire inhibitory function on other T cells, but their roles in controlling innate immune cells are poorly defined. As a potential cellular therapy for cancer, ex vivo activated CD4(+)Foxp3(-) effector T cells are often infused back in vivo to suppress tumor growth and metastasis. Whether such activated T cells could affect NK-cell control of tumorigenesis is unclear. In the present study, we found that mitogen-activated CD4(+)Foxp3(-) T cells exhibited potent suppressor function on NK-cell proliferation and cytotoxicity in vitro, and notably facilitated B16 melanoma metastasis in vivo. Suppression of NK cells by activated CD4(+)Foxp3(-) T cells is cell-cell contact dependent and is mediated by Qa-1:NKG2A interaction, as administration of antibodies blocking either Qa-1 or NKG2A could completely reverse this suppression, and significantly inhibited otherwise facilitated melanoma metastasis. Moreover, activated CD4(+)Foxp3(-) cells from Qa-1 knockout mice completely lost the suppressor activity on NK cells, and failed to facilitate melanoma metastasis when transferred in vivo. Taken together, our findings indicate that innate anti-tumor response is counter regulated by the activation of adaptive immunity, a phenomenon we term as "activation-induced inhibition". Thus, the regulatory role of activated CD4(+)Foxp3(-) T cells in NK-cell activity must be taken into consideration in the future design of cancer therapies.
小鼠 CD4(+)Foxp3(+)T 细胞对包括 NK 细胞在内的各种免疫细胞的调节作用已有充分的文献记载。在某些条件下，外周血中的常规 CD4(+)Foxp3(-)T 细胞能够获得对其他 T 细胞的抑制功能，但它们在控制固有免疫细胞方面的作用尚未明确。作为癌症的一种潜在细胞治疗方法，体外激活的 CD4(+)Foxp3(-)效应 T 细胞经常被输注回体内，以抑制肿瘤生长和转移。这种激活的 T 细胞是否能够影响 NK 细胞对肿瘤发生的控制尚不清楚。在本研究中，我们发现，丝裂原激活的 CD4(+)Foxp3(-)T 细胞在体外对 NK 细胞的增殖和细胞毒性具有强大的抑制作用，并且显著促进了 B16 黑色素瘤的转移。激活的 CD4(+)Foxp3(-)T 细胞通过细胞间接触抑制 NK 细胞，其机制是通过 Qa-1:NKG2A 相互作用，用阻断 Qa-1 或 NKG2A 的抗体进行治疗可完全逆转这种抑制作用，并显著抑制黑色素瘤的转移。此外，来自 Qa-1 敲除小鼠的激活的 CD4(+)Foxp3(-)细胞完全丧失了对 NK 细胞的抑制活性，并且在体内转移时未能促进黑色素瘤的转移。综上所述，我们的研究结果表明，固有抗肿瘤反应受到适应性免疫的激活的反向调节，我们将这种现象称为“激活诱导的抑制”。因此，在未来的癌症治疗设计中，必须考虑激活的 CD4(+)Foxp3(-)T 细胞对 NK 细胞活性的调节作用。
