Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor.

O Sascha Yousefi,Simon M Brandl,Matthias Günther,Maximilian Hörner,Tim Kunkel,Robert W Smith,Maximilian Wess,Thomas Höfer,Christian Fleck,Wilfried Weber,Wolfgang Wa Schamel,Matias D Zurbriggen,Julia Chalupsky

doi:10.7554/elife.42475

Abstract

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.

Highlights

The function of T cells is to mount an immune response to foreign ligands, such as derived from bacteria or viruses, but not to respond to self ligands stemming from the body’s own cells
Using continuous 660 nm light of different intensities to modulate the dynamics of phytochrome B (PhyB) tetramer binding to the T cell receptor (TCR) and calcium influx as a readout we find that there is an intensity threshold: at lower intensities and longer ligand-TCR half-lives the T cell is activated and at higher intensities and shorter half-lives the cell is not activated
The first aim of our study was to establish an optogenetic system in which ligand binding to the TCR can be reversibly controlled by light (Figure 1)

Summary

Introduction

The function of T cells is to mount an immune response to foreign ligands, such as derived from bacteria or viruses, but not to respond to self ligands stemming from the body’s own cells. These ligands are composed of a foreign peptide presented by major histocompatibility complexes molecules (pMHC) on the own cells. Self peptides on MHC (self pMHCs) bind to the TCR and are important for the development and survival of naıve T cells, but do not trigger an immune response as seen for foreign peptides on MHC (Davis et al, 1998). This discrimination between foreign and self pMHC correlates with the affinity of the ligand-TCR interaction, in that foreign, stimulatory pMHCs bind

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