Peripheral Vγ9/Vδ2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons

γδ T cells represent a minor population of human peripheral lymphocytes, the majority of them expressing the Vδ2/Vγ9 TCR. Their accumulation in infectious disease lesions and their reactivity toward mycobacterial Ags suggest that Vγ9/Vδ2 T cells play a role during infectious diseases. We have shown previously a significant expansion of the Vδ1 subset parallel to a dramatic decrease of the Vδ2 subset in PBMC from HIV-infected persons. To understand the mechanisms involved in the deletion of Vδ2 T cells, we analyzed their ability to respond in vitro to several Vγ9/Vδ2 T cell- specific ligands. We observed that in 60% of asymptomatic HIV-infected persons, Vδ2 T cells exhibited a functional anergy to Daudi and to Mycobacterium tuberculosis stimulations. These observations were supported by the defective expansion of this subset to the recently described nonpeptidic phosphorylated Ag, TUBAg-1. Since Vδ2 responsiveness to mycobacterial Ags was shown to be normally dependent on IL-2 secretion by Th1-type CD4 T cells, the ability of IL-2 to restore Vδ2 T cells' responsiveness to TUBAg-1 was tested. Vδ2 T cell anergy persisted in spite of the presence of IL-2, and was frequently correlated with a defect in CD25 expression on stimulated Vδ2 T cells. Since Vδ2 anergy was associated with an in vivo depletion of this subset, we studied whether programmed cell death could be involved in this process, particularly because of their activated phenotype. Although peripheral Vδ2 T cells from some HIV-infected persons showed an increased susceptibility to spontaneous and activation-induced apoptosis, statistical comparison between HIV+ and HIV- donors indicated that there was no difference between both groups in the rate of Vδ2 apoptosis. Finally, Vδ2 complementarity-determining region 3 TCR analysis indicated that, in vivo, the remaining Vδ2 T cells were still polyclonal. All together these results suggest that the qualitative and quantitative alterations of the Vδ2 subset in the course of HIV infection are the consequence of a chronic antigenic stimulation, and raise the question of the contribution of a cellular ligand induced or modified by chronic HIV infection.