title: Memory type 2 helper T cells induce long-lasting antitumor immunity by activating natural killer cells.
abstract: Functionally polarized helper T cells (Th cells) play crucial roles in the induction of tumor immunity. There is considerable knowledge about the contributions of IFN-producing Th1 cells that supports the role of cytotoxic cluster of differentiation (CD8) T cells and natural killer (NK) cells, but much less is known about how IL-4-producing Th2 cells contribute to tumor immunity. In this study, we investigated the cellular and molecular mechanisms employed by memory Th2 cells in sustaining tumor immunity by using a mouse model system wherein ovalbumin (OVA) is used as a specific tumor antigen. In this model, we found that OVA-specific memory Th2 cells exerted potent and long-lasting antitumor effects against NK-sensitive OVA-expressing tumor cells, wherein antitumor effects were mediated by NK cells. Specifically, NK cell cytotoxic activity and expression of perforin and granzyme B were dramatically enhanced by the activation of memory Th2 cells. Interleukin 4 (IL-4) produced by memory Th2 cells in vivo was critical for the antitumor effects of the NK cells, which IL-4 directly stimulated to induce their perforin- and granzyme-B-dependent cytotoxic activity. Our findings show that memory Th2 cells can induce potent antitumor immunity through IL-4-induced activation of NK cells, suggesting potential applications in cellular therapy for cancer patients.
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kitajima
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.forename: Damon J
authors.initials: DJ
authors.lastname: Tumes
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Endo
authors.forename: Atsushi
authors.initials: A
authors.lastname: Onodera
authors.forename: Kahoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Motohashi
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D011495:Histone-Lysine N-Methyltransferase; D007156:Immunologic Memory / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D051788:Myeloid-Lymphoid Leukemia Protein; D015847:Interleukin-4; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse