title: DNA-based nanoparticle tension sensors reveal that T-cell receptors transmit defined pN forces to their antigens for enhanced fidelity.
abstract: T cells are triggered when the T-cell receptor (TCR) encounters its antigenic ligand, the peptide-major histocompatibility complex (pMHC), on the surface of antigen presenting cells (APCs). Because T cells are highly migratory and antigen recognition occurs at an intermembrane junction where the T cell physically contacts the APC, there are long-standing questions of whether T cells transmit defined forces to their TCR complex and whether chemomechanical coupling influences immune function. Here we develop DNA-based gold nanoparticle tension sensors to provide, to our knowledge, the first pN tension maps of individual TCR-pMHC complexes during T-cell activation. We show that naïve T cells harness cytoskeletal coupling to transmit 12-19 pN of force to their TCRs within seconds of ligand binding and preceding initial calcium signaling. CD8 coreceptor binding and lymphocyte-specific kinase signaling are required for antigen-mediated cell spreading and force generation. Lymphocyte function-associated antigen 1 (LFA-1) mediated adhesion modulates TCR-pMHC tension by intensifying its magnitude to values >19 pN and spatially reorganizes the location of TCR forces to the kinapse, the zone located at the trailing edge of migrating T cells, thus demonstrating chemomechanical crosstalk between TCR and LFA-1 receptor signaling. Finally, T cells display a dampened and poorly specific response to antigen agonists when TCR forces are chemically abolished or physically "filtered" to a level below ∼12 pN using mechanically labile DNA tethers. Therefore, we conclude that T cells tune TCR mechanics with pN resolution to create a checkpoint of agonist quality necessary for specific immune response.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322;
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Lori
authors.initials: L
authors.lastname: Blanchfield
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322;
authors.forename: Victor Pui-Yan
authors.initials: VP
authors.lastname: Ma
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Rakieb
authors.initials: R
authors.lastname: Andargachew
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322;
authors.forename: Kornelia
authors.initials: K
authors.lastname: Galior
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Brian
authors.initials: B
authors.lastname: Evavold
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332 k.salaita@emory.edu.
authors.forename: Khalid
authors.initials: K
authors.lastname: Salaita
mesh_terms: D001696:Biomechanical Phenomena; D016827:CD8 Antigens / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage*; D006046:Gold; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D040542:Mechanotransduction, Cellular; D053768:Metal Nanoparticles / Q000008:administration & dosage*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*
chemical_list: D016827:CD8 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1; D006046:Gold; D004247:DNA; D002118:Calcium
keywords: T-cell receptor; antigen discrimination; cell migration; mechanotransduction; molecular tension sensor