Differential requirement of PKC-theta in the development and function of natural regulatory T cells.

CD4+CD25+ natural Treg cells, which are developed in the thymus, migrate to the periphery to actively maintain self-tolerance. Similar to conventional T cells, TCR signals are critical for the development and activation of Treg cell inhibitory function. While PKC-theta-mediated TCR signals are required for the activation of peripheral naïve T cells, they are dispensable for their thymic development. Here, we show that mice deficient in PKC-theta had a greatly reduced number of CD4+Foxp3+ Treg cells, which was independent of PKC-theta-regulated survival, as transgenic Bcl-x(L) could not restore the Treg cell population in PKC-theta(-/-) mice. Active and WT PKC-theta markedly stimulated, whereas inactive PKC-theta and dominant negative NFAT inhibited Foxp3 promoter activity. In addition, mice-deficient in calcineurin Abeta had a decreased Treg cell population, similar to that observed in PKC-theta deficient mice. It is likely that PKC-theta promoted the development of Treg cells by enhancing Foxp3 expression via activation of the calcineurin/NFAT pathway. Finally, Treg cells deficient in PKC-theta were as potent as WT Treg cells in inhibiting T cell activation, indicating that PKC-theta was not required for Treg cell-mediated inhibitory function. Our data highlight the contrasting roles PKC-theta plays in conventional T cell and natural Treg cell function.