title: The cellular environment regulates in situ kinetics of T-cell receptor interaction with peptide major histocompatibility complex.
abstract: T cells recognize antigens at the two-dimensional (2D) interface with antigen-presenting cells (APCs), which trigger T-cell effector functions. T-cell functional outcomes correlate with 2D kinetics of membrane-embedded T-cell receptors (TCRs) binding to surface-tethered peptide-major histocompatibility complex molecules (pMHCs). However, most studies have measured TCR-pMHC kinetics for recombinant TCRs in 3D by surface plasmon resonance, which differs drastically from 2D measurements. Here, we compared pMHC dissociation from native TCR on the T-cell surface to recombinant TCR immobilized on glass surface or in solution. Force on TCR-pMHC bonds regulated their lifetimes differently for native than recombinant TCRs. Perturbing the cellular environment suppressed 2D on-rates but had no effect on 2D off-rate regardless of whether force was applied. In contrast, for the TCR interacting with its monoclonal antibody, the 2D on-rate was insensitive to cellular perturbations and the force-dependent off-rates were indistinguishable for native and recombinant TCRs. These data present novel features of TCR-pMHC kinetics that are regulated by the cellular environment, underscoring the limitations of 3D kinetics in predicting T-cell functions and calling for further elucidation of the underlying molecular and cellular mechanisms that regulate 2D kinetics in physiological settings.
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Baoyu
authors.initials: B
authors.lastname: Liu
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA.
authors.forename: Kannan
authors.initials: K
authors.lastname: Natarajan
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Margulies
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.|Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.|Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D018448:Models, Immunological; D008958:Models, Molecular; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D010455:Peptides; D011948:Receptors, Antigen, T-Cell
keywords: Adhesion; Cellular immunology; Molecular immunology; T cells; TCRs