CD70-CD27 interactions provide survival and proliferative signals that regulate T cell receptor-driven activation of human gamma delta peripheral blood lymphocytes

Human V gamma 9V delta 2 T cells are potent anti-tumor lymphocytes that specifically respond to pyrophosphate (phospho-) antigens, which constitute the basis of current gamma delta T-cell-based immunotherapy strategies. Despite a clear involvement of the TCR, the costimulation requirements of V gamma 9V delta 2 T cells remain ill-defined. Here, we show that the expression of the CD27 receptor by the vast majority of V gamma 9V delta 2 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 gamma delta T cells. Moreover, V gamma 9V delta 2 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 V gamma 9V delta 2 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(+) V gamma 9V delta 2 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 gamma delta T-cell activation and hence open new perspectives for its modulation in clinical settings.