Forces generated by T cells augment antigen signaling
- Activation of T cells through TCR binding to antigen is a highly sensitive process. Recent evidence suggests triggering of the T cell receptor (TCR) integrates both binding kinetics and mechanical forces. To both measure and apply mechanical forces in real-time during T cell activation, I triggered T cells using a novel application of atomic force microscopy (AFM). Using cantilevers coated with antigen, I was able to deliver mechanical and chemical stimulation to T cells. T cells generate patterns of pushing and pulling forces during activation through rapid turnover of actin as well as myosin contractility. I demonstrate how the strength and duration of phases of force generation are regulated by the action of actin capping and severing proteins. In particular, I highlight the role of cofilin in generating pull forces and how it's activity can be regulated by Ca2+ levels. Loss of cell-generated forces through disruption of the cytoskeleton abrogated signaling. Emulation of these lost forces through movement of the AFM cantilever rescued signaling in these F-actin inhibited T cells. In addition, reducing the forces felt by T cells through force clamping of the cantilever decreased the sensitivity of T cells to low antigen concentrations. My work, taken with other findings, show that T cells generate forces during activation and a combination of these mechanical forces and biochemical ligation is required for optimal T cell activation. These studies suggest a mechanical—biochemical feedback loop in which TCR-triggered T cells generate forceful contacts with antigen-presenting cells to amplify signaling through TCR-pMHC engagements.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Hu, Kenneth Hsueh-heng
|Stanford University, Department of Biophysics.
|Butte, M. (Manish)
|Butte, M. (Manish)
|Statement of responsibility
|Kenneth Hsueh-heng Hu.
|Submitted to the Department of Biophysics.
|Thesis (Ph.D.)--Stanford University, 2017.
- © 2017 by Kenneth Hsueh-heng Hu
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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