Wang, XiaojuanCui, YanyanLuo, GaoxingWang, QinghongHu, JieHe, WeifengYuan, JunZhou, JunyiWu, YanSun, XRobson, SimonLi, XianchangTan, JianglingPeng, YanmengXue, GangLu, LinrongGao, WendaWu, Jun2013-04-242012Wang, Xiaojuan, Yanyan Cui, Gaoxing Luo, Qinghong Wang, Jie Hu, Weifeng He, Jun Yuan, et al. 2012. Activated mouse \(CD4^+Foxp3^−\) T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity. Cell Research 22(12): 1696-1706.1001-0602http://nrs.harvard.edu/urn-3:HUL.InstRepos:10582119The regulatory activities of mouse \(CD^4+Foxp3^+\) 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.en-USNK cellsT cellssuppressionmelanomametastasisQa-1Journal Article2013-04-2410.1038/cr.2012.128