title: TCRVγ9 γδ T Cell Response to IL-33: A CD4 T Cell-Dependent Mechanism.
abstract: The availability of specific stimuli to induce the anticancer cytotoxicity of human TCRVγ9-expressing T lymphocytes has allowed the development of γδ T cell-based cancer immunotherapies. However, the stringent dependence of such strategies on the inherently toxic IL-2 has raised safety concerns for patients, justifying a search for alternative methods for inducing γδ T cell stimulation. IL-33 is a γ-chain receptor-independent cytokine of the IL-1 superfamily that is expressed by endothelial cells from a tumor microenvironment and can sustain Th1 and Th2 immune responses. Therefore, we investigated its ability to support the stimulation of human TCRVγ9(+) γδ T cells. In this study, we report that IL-33 efficiently sustained the in vitro activation of Vγ9 T lymphocytes by synthetic phosphoantigens, zoledronate, and a BTN3A1 Ab in the absence of an exogenous supply of IL-2. IL-33 was as potent as IL-2 in allowing the proliferative amplification of Vγ9 T cells isolated from PBMC following activation by the synthetic phosphoantigen bromohydrin pyrophosphate. IL-33 also induced an identical maturation into TNF-α- and IFN-γ-producing Th1 effector memory cells, and IL-33-stimulated cells showed an equivalent cytotoxicity for various tumor cells in vitro. Finally, we found that the bioactivity of IL-33 on the Vγ9 T cell was indirectly mediated through contact with CD4 T cells and IL-2 production by CD4 T cells and Vγ9 T cells themselves. These data posit IL-33 as an alternative to IL-2 for Vγ9 T cell-based cancer immunotherapies.
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Duault
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and.
authors.forename: Don Marc
authors.identifier: http://orcid.org/0000-0002-2562-5643
authors.initials: DM
authors.lastname: Franchini
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and.
authors.forename: Julien
authors.identifier: http://orcid.org/0000-0001-8897-996X
authors.initials: J
authors.lastname: Familliades
authors.affiliation: Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Cayrol
authors.affiliation: Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors.forename: Stéphane
authors.identifier: http://orcid.org/0000-0003-3840-3887
authors.initials: S
authors.lastname: Roga
authors.affiliation: Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fournié
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, 31037 Toulouse, France; Université Toulouse III - Paul Sabatier, 31062 Toulouse, France; CNRS ERL 5294, 31024 Toulouse, France; TOUCAN Laboratoire d'Excellence Toulouse Cancer, 31024 Toulouse, France; and mary.poupot@inserm.fr.
authors.forename: Mary
authors.initials: M
authors.lastname: Poupot
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D000071797:Butyrophilins; D049109:Cell Proliferation; D002478:Cells, Cultured; D011756:Diphosphates / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000276:immunology / Q000627:therapeutic use; D000067596:Interleukin-33 / Q000276:immunology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000628:therapy*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077211:Zoledronic Acid
chemical_list: D015703:Antigens, CD; C558381:BTN3A1 protein, human; D000071797:Butyrophilins; D011756:Diphosphates; D004164:Diphosphonates; C508594:IL2 protein, human; C506536:IL33 protein, human; D007093:Imidazoles; D007376:Interleukin-2; D000067596:Interleukin-33; D016692:Receptors, Antigen, T-Cell, gamma-delta; C541125:TCRVgamma9 protein, human; D014409:Tumor Necrosis Factor-alpha; C429553:bromohydrin pyrophosphate; D000077211:Zoledronic Acid; D007371:Interferon-gamma