title: Triple costimulation via CD80, 4-1BB, and CD83 ligand elicits the long-term growth of Vγ9Vδ2 T cells in low levels of IL-2.
abstract: Human γδ T cells play important roles in the regulation of infection and cancer. To understand the roles of costimulatory signals in activation and expansion ex vivo, Vγ9Vδ2 T cells were grown with artificial APCs that express CD83, 4-1BB ligand, and/or CD32, which allowed a loading of αCD3 and αCD28 antibodies. The costimulatory signals through CD80, 4-1BB, and CD83 ligand in low levels of IL-2 triggered an explosive ex vivo proliferation of Vγ9Vδ2 T cells capable of secreting high levels of IL-2, IFN-γ, and TNF-α. Moreover, the triple-costimulatory signals cause augmented cell viabilities for long-term growth of Vγ9Vδ2 T cells, resulting in phenotypic changes to CD27(-)CD45RA(+) effector memory-like cells. Notably, we observed that CD83 ligand signaling is crucial to promote ex vivo expansion, survival, and cytolytic effector functions of Vγ9Vδ2 T cells. In contrast, 4-1BB signaling is moderately important in up-regulating surface molecules on Vγ9Vδ2 T cells. Consequently, γδ T cells stimulated in the presence of triple-costimulatory signals have diverse cytolytic effector molecules, including perforin, granzyme A, granzyme B, and Fas ligand, eliciting potent cytolytic activities against tumor cells. Overall, our results provide insights into the roles of costimulatory signals in manufacturing long-lived and fully functional Vγ9Vδ2 T cells that could be useful against cancers.
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Cho
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Su-Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Sohn
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Park
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Sohn
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea kimtg@catholic.ac.kr hyun.cho@catholic.ac.kr.
authors.forename: Hyun-Il
authors.initials: HI
authors.lastname: Cho
authors.affiliation: *Department of Microbiology, Catholic Hematopoietic Stem Cell Bank, and Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea kimtg@catholic.ac.kr hyun.cho@catholic.ac.kr.
authors.forename: Tai-Gyu
authors.initials: TG
authors.lastname: Kim
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology*; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D007136:Immunoglobulins; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000097802:CD83 Antigen; C508594:IL2 protein, human; C505714:TNFRSF9 protein, human
keywords: costimulatory signal; cytotoxicity; expansion; human γδ T cell