Activated mouse CD4＋Foxp3- T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity

• Published in: Cell research Vol. 22; no. 12; pp. 1696 - 1706
• Main Authors: Wang, Xiaojuan, Cui, Yanyan, Luo, Gaoxing, Wang, Qinghong, Hu, Jie, He, Weifeng, Yuan, Jun, Zhou, Junyi, Wu, Yan, Sun, Xiaofeng, Robson, Simon C, Li, Xianchang, Tan, Jiangling, Peng, Yanmeng, Xue, Gang, Lu, Linrong, Gao, Wenda, Wu, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2012; Nature Publishing Group
• Subjects: 631/250/2152; 631/67/322; 631/67/581; Animals; Antibodies - pharmacology; Biomedical and Life Sciences; CD4; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Biology; Cell Line, Tumor; Cell Proliferation; Cytotoxicity; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Immunosuppression; Killer Cells, Natural - cytology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Life Sciences; Lymphocyte Activation; Melanoma; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Knockout; Mice, Nude; Mice, SCID; Neoplasm Metastasis; NK Cell Lectin-Like Receptor Subfamily C - immunology; NK Cell Lectin-Like Receptor Subfamily C - metabolism; NK细胞; Original; original-article; Transplantation, Homologous; Tumors; T细胞; 体外活化; 依赖性; 小鼠; 细胞毒性; 黑色素瘤; suppression; melanoma; NK cells; Qa-1; T cells; metastasis
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2012.128

The regulatory activities of mouse CD4＋Foxp3＋ T cells on various immune cells, including NK ceils, have been well documented. Under some conditions, conventional CD4＋Foxp3- T cells in the periphery are able to acquire inhibi- tory 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-I：NKG2A interac- tion, 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.