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Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes
Published on: September 28, 2018
Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by
Tadashi Yokosuka1, Masako Takamatsu, Wakana Kobayashi-Imanishi
1Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan. yokosuka@rcai.riken.jp
Abstract:
Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1-mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1-TCR colocalization within microclusters is required for efficient PD-1-mediated suppression. This inhibitory mechanism also functions in PD-1(hi) T cells generated in vivo and can be overridden by a neutralizing anti-PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.
Insights
Programmed cell death 1 (PD-1) receptor clustering with T cell receptors (TCRs) suppresses T cell activation. This PD-1 microcluster formation is crucial for regulating immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Programmed cell death 1 (PD-1) is a key negative costimulatory receptor that suppresses T cell activation.
- Understanding the molecular mechanisms of PD-1-mediated T cell suppression is critical for immunotherapy development.
Purpose of the Study:
- To elucidate the molecular mechanism underlying PD-1-mediated suppression of T cell activation.
- To investigate the role of PD-1 clustering and colocalization with T cell receptors (TCRs) in this process.
Main Methods:
- Utilized single-cell imaging techniques to visualize PD-1 and TCR interactions.
- Analyzed the association of PD-1 with the phosphatase SHP2.
- Assessed the impact of PD-1 microclusters on TCR signaling and T cell activation.
Main Results:
- PD-1 clusters with TCRs upon binding to PD-L1, forming transient microclusters associated with SHP2.
- These microclusters induce dephosphorylation of proximal TCR signaling molecules, suppressing T cell activation.
- PD-1 and TCR colocalization within microclusters is essential for efficient suppression, which functions in PD-1(hi) T cells and can be blocked by anti-PD-L1 antibodies.
Conclusions:
- PD-1 microcluster formation, involving PD-1/TCR colocalization and SHP2 association, is a critical molecular mechanism for regulating T cell activation.
- This finding provides insights into the regulation of immune responses and potential therapeutic strategies targeting the PD-1 pathway.
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