• Interleukin‐18 activates Vγ9Vδ2+ T cells from HIV-positive individuals: recovering the response to phosphoantigen

      Murday, A.S.; Chaudhry, S.; Pauza, C.D. (Blackwell Publishing Ltd, 2017)
      The study aimed to identify an immunoregulatory factor that restores the phosphoantigen response of Vγ9Vδ2+ T cells from HIV‐positive individuals on antiretroviral therapy. It was designed to characterize the effects of interleukin‐18 (IL‐18) on proliferation and effector function in Vγ9Vδ2 T cells from HIV‐negative individuals and test whether exogenous IL‐18 reconstitutes the Vγ9Vδ2 T‐cell response to phosphoantigen from HIV‐positive donors. Vγ9Vδ2 T cells from HIV‐negative individuals responded strongly to phosphoantigen or aminobisphosphonate stimulation of peripheral blood mononuclear cells (PBMC), whereas cells with similar T‐cell receptor profiles from HIV‐positive individuals only responded to aminobisphosphonate. Interleukin‐18 was higher after aminobisphosphonate stimulation due to activation of the inflammasome pathway. Both IL‐18 and IL‐18 receptor levels were measured and the activity of exogenous IL‐18 on HIV‐negative and HIV‐positive PBMC was evaluated in terms of Vγ9Vδ2 T‐cell proliferation, memory subsets, cytokine expression and CD107a expression. Interleukin‐18 stimulation increased proliferation, enhanced the accumulation of effector memory cells, and increased expression of cytotoxic markers in HIV‐negative controls. When Vγ9Vδ2 T cells from HIV‐positive individuals were stimulated with isopentenyl pyrophosphate in the presence of IL‐18, there was increased proliferation, accumulation of memory cells, and higher expression of CD56, NKG2D and CD107a (markers of cytotoxic effector phenotype). Interleukin‐18 stimulation specifically expanded the Vγ9‐JγP+ subset of Vγ9Vδ2 T cells, as was expected for normal responses to phosphoantigen. Interleukin‐18 is a potent stimulator of Vγ9Vδ2 T‐cell proliferation and effector function. Therapies directed at reconstituting Vγ9Vδ2 T‐cell activity in HIV‐positive individuals should include stimulators of IL‐18 or direct cytokine supplementation.