title: Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands [corrected].
abstract: While much is known about intracellular signaling events in T cells when T cell receptors (TCRs) are engaged, the mechanism by which signaling is initiated is unclear. We have constructed defined oligomers of soluble antigen-major histocompatibility complex (MHC) molecules, the natural ligands for the TCR. Using these to stimulate specific T cells in vitro, we find that agonist peptide/MHC ligands are nonstimulatory as monomers and minimally stimulatory as dimers. Similarly, a partial-agonist ligand is very weakly active as a tetramer. In contrast, trimeric or tetrameric agonist ligands that engage multiple TCRs for a sustained duration are potent stimuli. Ligand-driven formation of TCR clusters seems required for effective activation and helps to explain the specificity and sensitivity of T cells.
authors.affiliation: Department of Microbiology and Immunology, Stanford University, California 94305, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Boniface
authors.forename: J D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: C
authors.initials: C
authors.lastname: Wülfing
authors.forename: J
authors.initials: J
authors.lastname: Hampl
authors.forename: Z
authors.initials: Z
authors.lastname: Reich
authors.forename: J D
authors.initials: JD
authors.lastname: Altman
authors.forename: R M
authors.initials: RM
authors.lastname: Kantor
authors.forename: C
authors.initials: C
authors.lastname: Beeson
authors.forename: H M
authors.initials: HM
authors.lastname: McConnell
authors.forename: M M
authors.initials: MM
authors.lastname: Davis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015374:Biosensing Techniques; D020013:Calcium Signaling; D019281:Dimerization; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011487:Protein Conformation; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D006649:Histocompatibility Antigens; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell