Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor
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.
The immune system distinguishes between self and foreign antigens. The kinetic proofreading 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 the kinetic proofreading model 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 the kinetic proofreading model.
