Foxp3-transduced polyclonal regulatory T cells suppress NK cell functions in a TGF-β dependent manner

Abstract

CD4⁺CD25⁺ regulatory T cells (Treg) are a unique population of T cells that maintain immune tolerance and are essential in host suppression of autoimmune diseases. Natural killer (NK) cells are an important component of the innate immune system and respond to insults. Recent studies demonstrate that NK cells may play a vital role during the onset and progression of certain autoimmune diseases. The decreased or abolished regulation by Treg cells on NK cells may lead to the abnormal autoimmune response. The purpose of this study was to investigate the suppressive effect of Foxp3-transduced CD4⁺ T cells on NK cell functions, and thus to present a possible method for managing NK cell-related autoimmune abnormalities. This study showed that forced Foxp3 expression in polyclonal CD4⁺ T cells could obtain Treg cells phenotype, including specifically expressing CD25, transforming growth factor (TGF-β) and CTLA-4. Since NK cells have two major immunological properties—cytotoxicity and cytokine production, we observed that transduction-induced Treg cells decreased NK cell cytotoxicity obviously, and dramatically downregulated the interferon-γ secretion of NK cell responding to IL-12 stimulation. Moreover, it was found that cell–cell interaction was essential for suppression of NK cell functions, and TGF-β played a vital role in the inhibition process. These results indicate that the forced Foxp3 expression in polyclonal CD4⁺ T cells could induce Treg cells and potentially inhibit NK cell functions.

Keywords::

• Regulatory T cells
• autoimmune diseases
• natural killer cells
• Foxp3
• immune suppression

Acknowledgements

We thank Prof. Warren S. Pear and Prof. Alexander Rudensky for kindly providing the MIGR1 and MIGR1-Foxp3 vector, respectively.

Declaration of interest: This work was supported partially by a grant from the Specialized Research Fund for the Doctoral Program of Chinese Higher Education (No. 200804871175), and partially by a grant from National Natural Science Foundation of China (No. 30571755). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.