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Blood, 22 January 2009, Vol. 113, No. 4, pp. 837-845.
Prepublished online as a Blood First Edition Paper on November 3, 2008; DOI 10.1182/blood-2008-06-162792.


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IMMUNOBIOLOGY

Phosphoantigen-activated V{gamma}2V{delta}2 T cells antagonize IL-2–induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Guangming Gong1,2,*, Lingyun Shao1,*, Yunqi Wang1,*, Crystal Y. Chen1, Dan Huang1, Shuyu Yao1, Ximei Zhan2, Helene Sicard3, Richard Wang1, and Zheng W. Chen1

1 Department of Microbiology and Immunology, Center for Primate Biomedical Research, College of Medicine, University of Illinois at Chicago; 2 Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China; and 3 Innate Pharma, Marseille, France

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 down-regulated 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-β 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}β T cells. Thus, phos-phoantigen 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.


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