The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we developed and tested a quantitative treatment of receptor triggering reliant only on TCR dwell time in phosphatase-depleted cell contacts constrained in area by cell topography. Using the model and experimentally derived parameters, we found that ligand discrimination likely depends crucially on individual contacts being ∼200 nm in radius, matching the dimensions of the surface protrusions used by T cells to interrogate their targets. The model not only correctly predicted the relative signaling potencies of known agonists and nonagonists but also achieved this in the absence of kinetic proofreading. Our work provides a simple, quantitative, and predictive molecular framework for understanding why TCR triggering is so selective and fast and reveals that, for some receptors, cell topography likely influences signaling outcomes.
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Mechanical feedback enables catch bonds to selectively stabilize scanning microvilli at T-cell surfaces
T-cells use microvilli to search the surfaces of antigen-presenting cells for antigenic ligands. The active motion of scanning microvilli provides a force-generating mechanism that is intriguing in light of single-molecule experiments showing that applied forces increase the lifetimes of stimulatory receptor–ligand bonds (catch-bond behavior). In this work, we introduce a theoretical framework to explore the motion of a microvillar tip above an antigen-presenting surface when receptors on the tip stochastically bind to ligands on the surface and dissociate from them in a force-dependent manner. Forces on receptor-ligand bonds impact the motion of the microvillus, leading to feedback between binding and microvillar motion. We use computer simulations to show that the average microvillar velocity varies in a ligand-dependent manner; that catch bonds generate responses in which some microvilli almost completely stop, while others move with a broad distribution of velocities; and that the frequency of stopping depends on the concentration of stimulatory ligands. Typically, a small number of catch bonds initially immobilize the microvillus, after which additional bonds accumulate and increase the cumulative receptor-engagement time. Our results demonstrate that catch bonds can selectively slow and stabilize scanning microvilli, suggesting a physical mechanism that may contribute to antigen discrimination by T-cells.
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- Award ID(s):
- 1753017
- NSF-PAR ID:
- 10188450
- Date Published:
- Journal Name:
- Molecular Biology of the Cell
- Volume:
- 30
- Issue:
- 16
- ISSN:
- 1059-1524
- Page Range / eLocation ID:
- 2087 to 2095
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Basic Protocol 1 : Protein and particle modification for aAPC fabricationBasic Protocol 2 : aAPC validation by immunolabeling of conjugated proteinSupport Protocol 1 : Quantification of aAPC stock concentrationBasic Protocol 3 : Determination of aAPC usage for murine CD8+T cell activationSupport Protocol 2 : Isolation of murine CD8+T cells -
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1091/mbc.E19-01-0048
