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

<div><p>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. <i>Mst1</i>^<i>-/-</i> Treg cells failed to prevent the development of experimental colitis and antigen-specific suppression of naïve T cells proliferation <i>in vitro</i>. <i>Mst1</i>^<i>-/-</i> Treg cells exhibited defective interactions with antigen-presenting dendritic cells (DCs), resulting in reduced down-regulation of costimulatory molecules. While wild-type CD4⁺ Foxp3⁺ Treg cells formed mobile immunological synapses on supported planar membrane, <i>Mst1</i>^<i>-/-</i> Treg cells 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 naïve T cells. In contrast, <i>Mst1</i>^<i>-/-</i> Treg had impairments in their interactions with DCs. Thus, Mst1 is required for Treg cells to mediate contact-dependent suppressor functions.</p>