Antigen-Specific Suppression and Immunological Synapse Formation by Regulatory T Cells Require the Mst1 Kinase.docVIP

Antigen-Specific Suppression and Immunological Synapse Formation by Regulatory T Cells Require the Mst1 Kinase Takashi Tomiyama , Yoshihiro Ueda , Tomoya Katakai , Naoyuki Kondo , Kazuichi Okazaki , Tatsuo 1,2 2 2 2 1 Kinashi 2* 1 Division of Gastroenterology and Hepatology, the Third Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan, 2 Department of Molecular Genetics, Institute of Biomedical Science, and Core Research for Engineering, Science and Technology, Japan Science and Technology Agency, Kansai Medical University, Hirakata, Osaka, Japan Abstract Although the cell-to-cell contact between CD4 Foxp3 regulatory T (Treg) and their target cells is important for the + + suppressor function of Treg cells, the regulation of this process is not well understood. Here we show that the Mst1 kinase plays a critical role in the suppressor function of Treg cells through regulation of cell contact dependent processes. Mst1 suppression of na?ve T cells proliferation in vitro. Mst1 presenting dendritic cells (DCs), resulting in reduced down-regulation of costimulatory molecules. While wild-type Treg cells formed mobile immunological synapses on supported planar membrane, Mst1 Treg cells -/- Treg cells failed to prevent the development of experimental colitis and antigen-specific -/- Treg cells exhibited defective interactions with antigen- CD4 + Foxp3 + -/- did not exhibit ICAM-1 ring or central peptide-MHC clustering. Using two-photon imaging we showed that antigen- specific wild-type Treg cells exhibited dynamic mobile contacts with antigen-pulsed DCs bearing stably associated -/- na?ve T cells. In contrast, Mst1 Treg had impairments in their inte