Activated mouse CD4+Foxp3- T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK cell cytotoxicity (127.17)

Abstract

Abstract 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 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 anti-tumor function is unclear. 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 Qa-1-blocking antibody could completely reverse this suppression, and significantly inhibited otherwise facilitated melanoma metastasis. Moreover, activated CD4+Foxp3- cells from Qa-1-/- 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, and thus the regulatory role of activated CD4+Foxp3- T cells in NK cell activity must be taken into consideration in the future design of anti-tumor biotherapies.