title: CD70-CD27 interactions provide survival and proliferative signals that regulate T cell receptor-driven activation of human γδ peripheral blood lymphocytes.
abstract: Human Vγ9Vδ2 T cells are potent anti-tumor lymphocytes that specifically respond to pyrophosphate (phospho-) antigens, which constitute the basis of current γδ T-cell-based immunotherapy strategies. Despite a clear involvement of the TCR, the costimulation requirements of Vγ9Vδ2 T cells remain ill-defined. Here, we show that the expression of the CD27 receptor by the vast majority of Vγ9Vδ2 peripheral blood lymphocytes endows them with enhanced proliferative capacity upon ligation by its unique ligand CD70, a tumor necrosis factor superfamily member expressed on lymphoma B-cells but also on TCR-activated γδ T cells. Moreover, Vγ9Vδ2 T-cell treatment with soluble recombinant CD70 induced calcium signals and increased transcription of anti-apoptotic Bcl2a1 and cell-cycle-promoting Cyclin D2 genes. We further demonstrate that the manipulation of CD70-CD27 interactions significantly impacted on Vγ9Vδ2 T-cell survival, proliferation and cytokine secretion, in both loss-of-function and gain-of-function experiments. Thus, CD27 coreceptor signals strongly promoted the expansion of Th1-biased, CD27(+) Vγ9Vδ2 peripheral blood lymphocytes in the context of TCR-mediated stimulation with phosphoantigens. These data collectively establish a novel role for the CD70-CD27 axis in human γδ T-cell activation and hence open new perspectives for its modulation in clinical settings.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: DeBarros
authors.forename: Miguel
authors.initials: M
authors.lastname: Chaves-Ferreira
authors.forename: Francisco
authors.initials: F
authors.lastname: d'Orey
authors.forename: Julie C
authors.initials: JC
authors.lastname: Ribot
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva-Santos
mesh_terms: D053282:CD27 Ligand / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D002450:Cell Communication; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D056742:Cyclin D2 / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation; D015778:Minor Histocompatibility Antigens; D009943:Organophosphorus Compounds / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
chemical_list: C096816:BCL2-related protein A1; D053282:CD27 Ligand; D056742:Cyclin D2; D016207:Cytokines; D007376:Interleukin-2; D015778:Minor Histocompatibility Antigens; D009943:Organophosphorus Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium