Related Experiment Video
Updated: May 17, 2026
Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
PD-1 signaling and PD-1 blockade-mediated tumor control are established at microvillar T cell contacts
Edward Jenkins1,2,3, Martin Fellermeyer1,2,4, Daniel F Heraghty5
1Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Abstract:
Lymphocyte activation relies on the integration of signals from multiple receptors at cell-cell contacts, but the spatiotemporal regulation of this process is unclear. Here, we show that programmed cell death protein 1 (PD-1) and T cell receptor (TCR) signals are integrated at nanoscale microvillar close contacts formed during T cell interactions with their targets. PD-1 signaling begins as these contacts form and selectively limits the duration, but not the amplitude, of TCR signaling. PD-1 suppresses TCR activity directly, by locally recruiting Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP2), and indirectly, by reducing cell-spreading, close-contact formation, and TCR engagement. A PD-1 blocking antibody induced inhibitory signaling when Fc receptor engagement trapped PD-1 at close contacts. Engineering the antibody to prevent PD-1 trapping eliminated these agonistic effects and improved blockade efficacy. These findings identify microvillar contacts as crucial hubs of initial signal integration and provide a framework for optimizing checkpoint immunotherapies.
Insights
Programmed cell death protein 1 (PD-1) limits T cell receptor (TCR) signaling duration at microvillar contacts. This discovery offers a framework for enhancing cancer immunotherapy efficacy.
Area of Science:
- Immunology
- Cell Biology
- Molecular Signaling
Background:
- Lymphocyte activation integrates signals from multiple receptors at cell-cell contacts.
- The spatiotemporal regulation of immune cell signaling integration remains poorly understood.
Purpose of the Study:
- To investigate the spatiotemporal integration of programmed cell death protein 1 (PD-1) and T cell receptor (TCR) signaling.
- To elucidate the role of microvillar contacts in immune signal integration.
Main Methods:
- Live-cell imaging of T cell-target cell interactions.
- Analysis of PD-1 and TCR signaling dynamics.
- Biochemical assays involving SHP2 recruitment.
- Engineering of PD-1 blocking antibodies.
Main Results:
- PD-1 and TCR signals integrate at nanoscale microvillar contacts.
- PD-1 signaling limits the duration, not amplitude, of TCR signaling.
- PD-1 suppresses TCR activity by recruiting SHP2 and reducing cell spreading and TCR engagement.
- Antibody engineering to prevent PD-1 trapping improved blockade efficacy.
Conclusions:
- Microvillar contacts are critical hubs for initial immune signal integration.
- Understanding PD-1/TCR interaction dynamics at contacts optimizes checkpoint immunotherapies.
- Targeted antibody design can enhance the efficacy of PD-1 blockade.
Related Concept Videos
01:27Tumor Immunotherapy
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:17The Tumor Microenvironment