Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany
Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany; BioQuant Center, University of Heidelberg, Heidelberg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
Julia Chalupsky
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center Freiburg and Faculty of Medicine, University of Freiburg, Freiburg, Germany
Maximilian Wess
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
Simon M Brandl
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
Laboratory of Systems and Synthetic Biology, Wageningen University and Research, Wageningen, Netherlands
Christian Fleck
Laboratory of Systems and Synthetic Biology, Wageningen University and Research, Wageningen, Netherlands
Tim Kunkel
Faculty of Biology, University of Freiburg, Freiburg, Germany
Matias D Zurbriggen
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Institute of Synthetic Biology and Cluster of Excellence on Plant Sciences, University of Düsseldorf, Düsseldorf, Germany
Thomas Höfer
Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany; BioQuant Center, University of Heidelberg, Heidelberg, Germany
Wilfried Weber
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Laboratory of Systems and Synthetic Biology, Wageningen University and Research, Wageningen, Netherlands
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.
