Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2-induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Although Foxp3(+) T regulatory cells (Tregs) are well documented for their ability to suppress various immune cells, T-cell subsets capable of counteracting Tregs have not been demonstrated. Here, we assessed phosphoantigen-activated V gamma 2V delta 2 T cells for the ability to interplay with Tregs in the context of mycobacterial infection. A short-term IL-2 treatment regimen induced marked expansion of CD4(+)CD25(+)Foxp3(+) T cells and subsequent suppression of mycobacterium-driven increases in numbers of V gamma 2V delta 2 T cells. Surprisingly, activation of V gamma 2V delta 2 T cells by adding phosphoantigen Picostim to the IL-2 treatment regimen downregulated IL-2-induced expansion of CD4(+)CD25(+)Foxp3(+) T cells. Consistently, in vitro activation of V gamma 2V delta 2 T cells by phosphoantigen plus IL-2 down-regulated IL-2 induced expansion of CD4(+)CD25(+)Foxp3(+) T cells. Interestingly, anti-IFN-gamma-neutralizing antibody, not anti-TGF-beta or anti-IL-4, reduced the ability of activated V gamma 2V delta 2 T cells to down-regulate Tregs, suggesting that autocrine IFN-gamma and its network contributed to V gamma 2V delta 2 T cells antagonizing effects. Furthermore, activation of V gamma 2V delta 2 T cells by Picostim plus IL-2 treatment appeared to reverse Treg-driven suppression of immune responses of phosphoantigen-specific IFN gamma(+) or perforin(+) V gamma 2V delta 2 T cells and PPD-specific IFN gamma(+)alpha beta T cells. Thus, phosphoantigen activation of V gamma 2V delta 2 T cells antagonizes IL-2-induced expansion of Tregs and subsequent suppression of Ag-specific antimicrobial T-cell responses in mycobacterial infection. (Blood. 2009;113:837-845)