PERIPHERAL V-GAMMA-9 V-DELTA-2 T-CELL DELETION AND ANERGY TO NONPEPTIDIC MYCOBACTERIAL ANTIGENS IN ASYMPTOMATIC HIV-1-INFECTED PERSONS/

gamma delta T cells represent a minor population of human peripheral l ymphocytes, the majority of them expressing the V delta 2/V gamma 9 TC R. Their accumulation in infectious disease lesions and their reactivi ty toward mycobacterial Ags suggest that V gamma 9/V delta 2 T cells p lay a role during infectious diseases. We have shown previously a sign ificant expansion of the V delta 1 subset parallel to a dramatic decre ase of the V delta 2 subset in PBMC from HIV-infected persons. To unde rstand the mechanisms involved in the deletion of V delta 2 T cells, w e analyzed their ability to respond in vitro to several V gamma 9/V de lta 2 T cell-specific ligands. We observed that in 60% of asymptomatic HIV-infected persons, V delta 2 T cells exhibited a functional anergy to Daudi and to Mycobacterium tuberculosis stimulations. These observ ations were supported by the defective expansion of this subset to the recently described nonpeptidic phosphorylated Ag, TUBAg-1. Since V de lta 2 responsiveness to mycobacterial Ags was shown to be normally dep endent on IL-2 secretion by Th1-type CD4 T cells, the ability of IL-2 to restore V delta 2 T cells' responsiveness to TUBAg-1 was tested. V delta 2 T cell anergy persisted in spite of the presence of IL-2, and was frequently correlated with a defect in CD25 expression on stimulat ed V delta 2 T cells. Since V delta 2 anergy was associated with an in vivo depletion of this subset, we studied whether programmed cell dea th could be involved in this process, particularly because of their ac tivated phenotype. Although peripheral V delta 2 T cells from some HIV -infected persons showed an increased susceptibility to spontaneous an d activation-induced apoptosis, statistical comparison between HIV+ an d HIV- donors indicated that there was no difference between both grou ps in the rate of V delta 2 apoptosis. Finally, V delta 2 complementar y-determining region 3 TCR analysis indicated that, in vivo, the remai ning V delta 2 T cells were still polyclonal. All together these resul ts suggest that the qualitative and quantitative alterations of the V delta 2 subset in the course of HIV infection are the consequence of a chronic antigenic stimulation, and raise the question of the contribu tion of a cellular ligand induced or modified by chronic HIV infection .