title: T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand.
abstract: The binding of a T-cell antigen receptor (TCR) to peptide antigen presented by major histocompatibility antigens (pMHC) on antigen-presenting cells (APCs) is a central event in adaptive immune responses. The mechanism by which TCR-pMHC ligation initiates signalling, a process termed TCR triggering, remains controversial. It has been proposed that TCR triggering is promoted by segregation at the T cell-APC interface of cell-surface molecules with small ectodomains (such as TCR-pMHC and accessory receptors) from molecules with large ectodomains (such as the receptor protein tyrosine phosphatases CD45 and CD148). Here we show that increasing the dimensions of the TCR-pMHC interaction by elongating the pMHC ectodomain greatly reduces TCR triggering without affecting TCR-pMHC ligation. A similar dependence on receptor-ligand complex dimensions was observed with artificial TCR-ligand systems that span the same dimensions as the TCR-pMHC complex. Interfaces between T cells and APCs expressing elongated pMHC showed an increased intermembrane separation distance and less depletion of CD45. These results show the importance of the small size of the TCR-pMHC complex and support a role for size-based segregation of cell-surface molecules in TCR triggering.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Choudhuri
authors.forename: David
authors.initials: D
authors.lastname: Wiseman
authors.forename: Marion H
authors.initials: MH
authors.lastname: Brown
authors.forename: Keith
authors.initials: K
authors.lastname: Gould
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000737:chemistry / Q000276:immunology; D016466:CHO Cells; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D006649:Histocompatibility Antigens / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D010455:Peptides / Q000737:chemistry* / Q000276:immunology*; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000941:Antigens; D006649:Histocompatibility Antigens; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D017493:Leukocyte Common Antigens