title: Activated mouse CD4(+)Foxp3(-) T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity.
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 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.
authors.affiliation: 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.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cui
authors.forename: Gaoxing
authors.initials: G
authors.lastname: Luo
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Weifeng
authors.initials: W
authors.lastname: He
authors.forename: Jun
authors.initials: J
authors.lastname: Yuan
authors.forename: Junyi
authors.initials: J
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Sun
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Xianchang
authors.initials: X
authors.lastname: Li
authors.forename: Jiangling
authors.initials: J
authors.lastname: Tan
authors.forename: Yanmeng
authors.initials: Y
authors.lastname: Peng
authors.forename: Gang
authors.initials: G
authors.lastname: Xue
authors.forename: Linrong
authors.initials: L
authors.lastname: Lu
authors.forename: Wenda
authors.initials: W
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007165:Immunosuppression Therapy; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology / Q000378:metabolism; D009362:Neoplasm Metastasis; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; C032907:Q surface antigens