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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Inhibitory TIGIT signaling is dependent on T cell receptor activation
William H Zammit1, Lucy J Le Maistre2, Thomas A E Elliot2
1Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Manchester Cell-Matrix Centre, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Cell Reports
|August 6, 2026
Summary
The immune checkpoint receptor TIGIT (T cell immunoreceptor with Ig and ITIM domains) signals through CD155 engagement and T cell receptor activation. This interaction regulates T cell function by recruiting specific signaling and endocytosis proteins.
Area of Science:
- Immunology
- Cellular Signaling
- Molecular Biology
Background:
- The immune checkpoint receptor TIGIT regulates T cell function through cytoplasmic signaling motifs.
- The specific signaling molecules and regulatory mechanisms of TIGIT remain incompletely understood.
Purpose of the Study:
- To identify proteins proximal to TIGIT upon CD155 engagement.
- To elucidate the molecular mechanisms regulating TIGIT signaling and its dependence on T cell receptor (TCR) activation.
Main Methods:
- Proximity proteomics was utilized to identify TIGIT-interacting proteins.
- Crosslinking followed by immunoprecipitation confirmed direct protein-protein interactions.
- Mutagenesis of TIGIT was employed to assess the role of specific residues in signaling.
Main Results:
- Several ligation-specific proteins, including Grb2, SOS1, CD2AP, SdcBP, IST1, and SNX3, were identified proximal to TIGIT.
- A direct interaction between TIGIT and CD2AP was demonstrated.
- TCR stimulation was found to be essential for TIGIT to engage with signaling pathways.
- Phosphorylation and internalization of TIGIT were dependent on both CD155 ligation and TCR activation.
Conclusions:
- TIGIT signaling is tightly regulated by CD155 engagement and requires TCR activation.
- This TCR-dependent mechanism ensures TIGIT-mediated immune checkpoint control is functionally relevant.
- The identified TIGIT-proximal proteins offer new insights into T cell regulation by immune checkpoints.
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