Interleukin-18 activates Vγ9Vδ2+T cells from HIV-positive individuals: recovering the response to phosphoantigen.
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.
Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Alanna S
AS
Murday
Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Suchita
S
Chaudhry
Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
C David
0000-0002-0559-793X
CD
Pauza
D000941:Antigens / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004164:Diphosphonates / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D045782:Hemiterpenes / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007156:Immunologic Memory; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods*; D020382:Interleukin-18 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D009943:Organophosphorus Compounds / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D000077211:Zoledronic Acid
D000941:Antigens; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D020382:Interleukin-18; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid
Vγ9Vδ2; human immunodeficiency virus; inflammasome; interleukin-18; phosphoantigen; γδ T cell