title: 2D TCR-pMHC-CD8 kinetics determines T-cell responses in a self-antigen-specific TCR system.
abstract: Two-dimensional (2D) kinetic analysis directly measures molecular interactions at cell-cell junctions, thereby incorporating inherent cellular effects. By comparison, three-dimensional (3D) analysis probes the intrinsic physical chemistry of interacting molecules isolated from the cell. To understand how T-cell tumor reactivity relates to 2D and 3D binding parameters and to directly compare them, we performed kinetic analyses of a panel of human T-cell receptors (TCRs) interacting with a melanoma self-antigen peptide (gp100209 -217 ) bound to peptide-major histocompatibility complex in the absence and presence of co-receptor CD8. We found that while 3D parameters are inadequate to predict T-cell function, 2D parameters (that do not correlate with their 3D counterparts) show a far broader dynamic range and significantly improved correlation with T-cell function. Thus, our data support the general notion that 2D parameters of TCR-peptide-major histocompatibility complex-CD8 interactions determine T-cell responsiveness and suggest a potential 2D-based strategy to screen TCRs for tumor immunotherapy.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Baoyu
authors.initials: B
authors.lastname: Liu
authors.forename: Shi
authors.initials: S
authors.lastname: Zhong
authors.forename: Karolina
authors.initials: K
authors.lastname: Malecek
authors.forename: Laura A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
mesh_terms: D016827:CD8 Antigens / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D058951:gp100 Melanoma Antigen / Q000276:immunology / Q000378:metabolism
chemical_list: D016827:CD8 Antigens; D015789:HLA-A2 Antigen; C548637:PMEL protein, human; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen
keywords: 2D kinetics; Micropipette adhesion frequency assay; T-cell activation; Thermal fluctuation assay