A simple twist of phosphate: Immunological synapse formation and T cell receptor signaling outcome in regulatory T cells.

Signaling through the T cell receptor (TCR) regulates T cell homeostasis and effector functions. However, a full accounting of the TCR-coupled signaling networks and how their interplay determines specific functional outcomes remains elusive. Of particular interest are efforts over the last years to elucidate distinctive features of TCR signaling in regulatory T cells (Treg) that may account for some of their unique functional attributes as compared to conventional T (Tconv) cells. In this issue of the European Journal of Immunology, van Ham et al. [Eur. J. Immunol. 2017. 47: 2043-2058] employed differential phosphoproteomics to identify a set of 11 proteins mainly linked to cytoskeletal organization and molecular transport that discriminate between TCR signaling in the respective cell subset. They further linked these differences to cell subset-specific alterations in the spatio-temporal organization of signaling pathways at immune synapse (IS) in Treg versus T conv. These data support the idea that these proteins may act as a molecular "twist" element driving Treg cell-specific responses by affecting cytoskeletal dynamics and IS formation. Taken together, these findings may facilitate the development of novel immunomodulatory agents that exploit differences in TCR signaling between Treg and Tconv cells.