title: Receptor proximity, not intermolecular orientation, is critical for triggering T-cell activation.
abstract: Engagement of antigen receptors on the surface of T-cells with peptides bound to major histocompatibility complex (MHC) proteins triggers T-cell activation in a mechanism involving receptor oligomerization. Receptor dimerization by soluble MHC oligomers is sufficient to induce several characteristic activation processes in T-cells including internalization of engaged receptors and up-regulation of cell surface proteins. In this work, the influence of intermolecular orientation within the activating receptor dimer was studied. Dimers of class II MHC proteins coupled in a variety of orientations and topologies each were able to activate CD4+ T-cells, indicating that triggering was not dependent on a particular receptor orientation. In contrast to the minimal influence of receptor orientation, T-cell triggering was affected by the inter-molecular distance between MHC molecules, and MHC dimers coupled through shorter cross-linkers were consistently more potent than those coupled through longer cross-linkers. These results are consistent with a mechanism in which intermolecular receptor proximity, but not intermolecular orientation, is the key determinant for antigen-induced CD4+ T-cell activation.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Cochran
authors.forename: T O
authors.initials: TO
authors.lastname: Cameron
authors.forename: J D
authors.initials: JD
authors.lastname: Stone
authors.forename: J B
authors.initials: JB
authors.lastname: Lubetsky
authors.forename: L J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015798:HLA-DR1 Antigen / Q000096:biosynthesis / Q000737:chemistry; D006801:Humans; D008213:Lymphocyte Activation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014867:Water / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D015798:HLA-DR1 Antigen; D010455:Peptides; D011994:Recombinant Proteins; D014867:Water