Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor
Authors: Yousefi OS, Günther M, Hörner M, Chalupsky J, Wess M, Brandl SM, Smith RW, Fleck C, Kunkel T, Zurbriggen MD, Höfer T, Weber W, Schamel WW
CellNetworks People: Höfer Thomas
Journal: Elife. 2019 Apr 5;8. pii: e42475. doi: 10.7554/eLife.42475

The immune system distinguishes between self and foreign antigens. The kinetic proofreading (KPR) model proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B (PhyB) as a ligand to selectively control the dynamics of ligand binding to the TCR by light. This opto-ligand-TCR system was combined with the unique property of PhyB to continuously cycle between the binding and non-binding states under red light, with the light intensity determining the cycling rate and thus the binding duration. Mathematical modeling of our experimental datasets showed that indeed the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating KPR.