Regulation by cytokines (IL‐12, IL‐15, IL‐4 and IL‐10) of the Vγ9Vδ2 T cell response to mycobacterial phosphoantigens in responder and anergic HIV‐infected persons

Human Vγ9Vδ2 T cells contribute to immunity against intracellular pathogens and recognize nonpeptidic antigens, such as the mycobacterial phosphoantigen TUBAg. HIV infection is associated with a polyclonal decrease of peripheral Vγ9Vδ2 T cells and we previously reported that the remaining cells show a proliferative anergy to stimulation with Mycobacterium tuberculosis in 60 % of patients. Because of alterations in the Th1/Th2 cytokine balance reported in HIV infection, we analyzed, at the single‐cell level, the influence of exogenous IL‐4, IL‐10, IL‐12 and IL‐15 on the response to mycobacterial phosphoantigens of γ δ T cells from HIV‐infected patients and healthy donors. We report that the strong γ δ T cell response to TUBAg is characterized by the rapid and selective production of the Th1/proinflammatory cytokines IFN‐γ and TNF‐α in responder HIV‐infected donors. In addition, a positive regulation by IL‐12 and IL‐15 of the production of these cytokines by Vγ9Vδ2 T cells in response to nonpeptidic ligands was observed, whereas IL‐4 and IL‐10 had no effect. In contrast, Vγ9Vδ2 T cells from the anergic HIV‐infected donors had lost the ability to produce Th1 cytokines and were not shifted towards a Th2 profile. Furthermore, neither IL‐12 nor IL‐15 could reverse this functional anergy. The consequences of these observations are discussed in the context of HIV pathogenesis.