Regulation by cytokines (IL-12, IL-15, IL-4 and IL-10) of the V gamma 9V delta 2 T cell response to mycobacterial phosphoantigens in responder and anergic HIV-infected persons

Human V gamma 9V delta 2 T cells contribute to immunity against intracellul ar pathogens and recognize nonpeptidic antigens, such as the mycobacterial phosphoantigen TUBAg. HIV infection is associated with a polyclonal decreas e of peripheral V gamma 9V delta 2 T cells and we previously reported that the remaining cells show a proliferative anergy to stimulation with Mycobac terium 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 mycobacteria[ phosphoantigens of gamma delta T cells from HIV-i nfected patients and healthy donors. We report that the strong gamma delta T cell response to TUBAS is characterized by the rapid and selective produc tion of the Thl/proinflammatory cytokines IFN-gamma and TNF-alpha in respon der HIV-infected donors. In addition, a positive regulation by IL-12 and IL -15 of the production of these cytokines by V gamma 9V delta 2 T cells in r esponse to nonpeptidic ligands was observed, whereas IL-4 and IL-10 had no effect. In contrast, V gamma 9V delta 2 T cells from the anergic HIV-infect ed donors had lost the ability to produce Th1 cytokines and were not shifte d towards a Th2 profile. Furthermore, neither IL-12 nor IL-15 could reverse this functional anergy. The consequences of these observations are discuss ed in the context of HIV pathogenesis.