Αβ T Cell Receptor Mechanosensing Forces out Serial Engagement. Issue 8 (August 2018)

• Record Type: Journal Article
• Authors: Feng, Yinnian; Reinherz, Ellis L.; Lang, Matthew J.
• Is Part Of: Trends in immunology. Volume 39:Issue 8(2018)
• Page Start: 596
• Page End: 609
• Publication Date: 2018-08
• Subjects: Immunology -- Periodicals; 571.96
• DOI: 10.1016/j.it.2018.05.005
• Languages: English
• ISSNs: 1471-4906

Abstract

Abstract : T lymphocytes use αβ T cell receptors (TCRs) to recognize sparse antigenic peptides bound to MHC molecules (pMHCs) arrayed on antigen-presenting cells (APCs). Contrary to conventional receptor–ligand associations exemplified by antigen–antibody interactions, forces play a crucial role in nonequilibrium mechanosensor-based T cell activation. Both T cell motility and local cytoskeleton machinery exert forces (i.e., generate loads) on TCR–pMHC bonds. We review biological features of the load-dependent activation process as revealed by optical tweezers single molecule/single cell and other biophysical measurements. The findings link pMHC-triggered TCRs to single cytoskeletal motors; define the importance of energized anisotropic (i.e., force direction dependent) activation; and characterize immunological synapse formation as digital, revealing no serial requirement. The emerging picture suggests new approaches for the monitoring and design of cytotoxic T lymphocyte (CTL)-based immunotherapy. Highlights: The αβ TCR is a mechanosensor whose force-dependent structural transition and allostery regulate peptide discrimination and pMHC bond lifetime. Application of mechanical force on the TCR during ligand recognition promotes its molecular translocation and initiates T cell immunological synapse formation. Synergy of external (cell motility based) and internal (cytoskeletal motor based) forces supports a nonequilibrium (energized) model for T cell activation through reconfiguration of the αβ TCR complex at a critical force threshold. A digital mechanosensing mechanism defines physicochemical thresholds with significant implications for CTL-based vaccines and immunotherapies. That knowledge affords new insights relative to earlier αβ TCR activation models based on equilibrium processes.