Protein kinase C-theta interacts with mTORC2 and vimentin to limit regulatory T-cell function
McDonald-Hyman C., Thangavelu G., Muller J., Zhang G., Kumari S., Saha A., Koehn BH., Mitchell JS., Fife BT., Serody JS., Osborn MJ., Hippen KL., Kelekar A., Munn DH., Altman A., Neubert TA., Dustin M., Blazar BR.
Regulatory T-cells (Tregs) play a critical role in preventing autoimmune and alloimmune reactions, including graft-versus-host disease (GVHD). Two recent clinical trials demonstrated that in patients undergoing hematopoietic stem cell transplantation, adoptive transfer of Tregs significantly reduced the incidence of grades II-IV GVHD. While Tregs significantly reduced GVHD severity, they did not eliminate GVHD. One potential way to augment Treg-mediated inhibition of GVHD is to increase Treg suppressive potency. We showed previously that Tregspecific inhibition of protein kinase C-theta (PKC-θ) enhances Treg function (Science 328:372, 2010). However, it is unclear whether PKC-θinhibition can boost Treg function in a systemic inflammatory condition like GVHD. Furthermore, the mechanism by which PKC-θinhibition augments Treg function is unknown. In this study, we address these unanswered questions.