Regulatory T Cells Suppress Natural Killer Cells during Plasmid DNA Vaccination in Mice, Blunting the CD8+ T Cell Immune Response by the Cytokine TGFβ

Abstract

BackgroundCD4+CD25+ regulatory T cells (Tregs) suppress adaptive T cell-mediated immune responses to self- and foreign-antigens. Tregs may also suppress early innate immune responses to vaccine antigens and might decrease vaccine efficacy. NK and NKT cells are the first responders after plasmid DNA vaccination and are found at the site of inoculation. Earlier reports demonstrated that NKT cells could improve plasmid DNA efficacy, a phenomenon not found for NK cells. In fact, it has been shown that under certain disease conditions, NK cells are suppressed by Tregs via their release of IL-10 and/or TGFβ. Therefore, we tested the hypothesis that NK cell function is suppressed by Tregs in the setting of plasmid DNA vaccination.Methodology/Principal FindingsIn this study we show that Tregs directly inhibit NK cell function during plasmid DNA vaccination by suppressing the potentially 10-fold, NK cell-mediated, augmentation of plasmid DNA antigen-specific CD8+ T cells. We found that this phenomenon is dependent on the secretion of cytokine TGFβ by Tregs, and independent of IL-10.ConclusionsOur data indicate a crucial function for Tregs in blocking plasmid DNA vaccine-elicited immune responses, revealing potentially novel strategies for improving the efficiency of plasmid DNA vaccines including chemical- or antibody-induced localized blockage of Treg-mediated suppression of NK cells at the site of plasmid DNA vaccine inoculation.

Human tumor‐induced and naturally occurring Treg cells differentially affect NK cells activated by either IL‐2 or target cells

“…These effects were significantly impaired in the presence of tumor iTreg cells, nTreg cells or TGF-b. Our results are in agreement with published reports, where other types of Treg cells were described to suppress NK cell functions under various experimental conditions, in most instances in a TGF-b-dependent manner [11,12,19,[23][24][25][26][27]. Unexpectedly, we found that degranulation and the subsequent tumoricidal activity of naive NK cells were enhanced by iTreg cells.…”

Synergistic and Additive Effects of Cimetidine and Levamisole on Cellular Immune Responses to Hepatitis B virus DNA Vaccine in Mice

“…In vivo , the Treg inhibitor effects are mediated by TGF‐β and IL‐10. Thus, the blockade or elimination of Treg or their release of TGF‐β and IL‐10 augment plasmid DNA antigen‐specific CD4 + and CD8 + T cells, especially CTLs . Consistent with our previous study , although CIM did not alter the frequency of Treg, it inhibited TGF‐β and IL‐10 production in CD4 + CD25 + T cells suggesting that CIM inhibits Treg‐mediated suppressive function.…”

Polyphenol E Enhances the Antitumor Immune Response in Neuroblastoma by Inactivating Myeloid Suppressor Cells

“…Myeloid cells hamper the function of not only T, but also natural killer (NK), cells, which are known to be essential for the effect of the ch14.18 antibody (30,31). Furthermore, it is known that tumor-induced Tregs blunt the NK and CD4/CD8 T-cell immune response elicited by different forms of vaccination (28,32). Thus, we hypothesize that the increased numbers of myeloid cells in the blood of patients with neuroblastoma could interfere with the antitumor immune response and explain the failure of a significant proportion of patients to respond to immunotherapy (27).…”