EBV-induced human CD8+ NKT cells suppress tumorigenesis by EBV-associated malignancies.
The underlying mechanism of the protective and suppressive role of NKT cells in human tumor immunosurveillance remains to be fully elucidated. We show that the frequencies of CD8(+) NKT cells in patients with EBV-associated Hodgkin's lymphoma or nasopharyngeal carcinoma are significantly lower than those in healthy EBV carriers. These CD8(+) NKT cells in tumor patients are also functionally impaired. In human-thymus-severe combined immunodeficient (hu-thym-SCID) chimeras, EBV challenge efficiently promotes the generation of IFN-gamma-biased CD8(+) NKT cells. These cells are strongly cytotoxic, drive syngeneic T cells into a Th1 bias, and enhance T-cell cytotoxicity to EBV-associated tumor cells. Interleukin-4-biased CD4(+) NKT cells are predominately generated in unchallenged chimeras. These cells are noncytotoxic, drive syngeneic T cells into a Th2 bias, and do not affect T-cell cytotoxicity. In humanized xenogeneic tumor-transplanted hu-thym-SCID chimeras, adoptive transfer with EBV-induced CD8(+) NKT cells significantly suppresses tumorigenesis by EBV-associated malignancies. EBV-induced CD8(+) NKT cells are necessary and sufficient to enhance the T-cell immunity to EBV-associated malignancies in the hu-thym-SCID chimeras. CD4(+) NKT cells are synergetic with CD8(+) NKT cells, leading to a more pronounced T-cell antitumor response in the chimeras cotransferred with CD4(+) and CD8(+) NKT cells. Thus, immune reconstitution with EBV-induced CD8(+) NKT cells could be a useful strategy in management of EBV-associated malignancies.
Yuling
He
H
Department of Immunology, and Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-related Diseases, Center for Medical Research, Wuhan University School of Medicine, Wuhan, People's Republic of China.
Ruijing
Xiao
X
Li
Li
L
Xiang
Ji
J
Rui
Zhou
Z
Yujuan
Wang
W
Lijun
Zhang
Z
Chunxian
Du
D
Xinti
Tan
T
Wei
Xiao
X
Lang
Chen
C
Yanping
Jiang
J
Tao
Xiong
X
Mengjun
Wu
W
Jie
Xiong
X
Youxin
Jin
J
Jinquan
Tan
T
D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002678:Chimera / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006689:Hodgkin Disease / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009303:Nasopharyngeal Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma