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

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.