Abstract During T cell activation, the engagement of costimulatory molecules is often crucial to the development of an effective immune response, but the mechanism by which this is achieved is not known. Here, it is shown that beads attached to the surface of a T cell translocate toward the interface shortly after the start of T cell activation. This movement appears to depend on myosin motor proteins and requires the engagement of the major costimulatory receptor pairs, B7-CD28 and ICAM-1–LFA-1. This suggests that the engagement of costimulatory receptors triggers an active accumulation of molecules at the interface of the T cell and the antigen-presenting cell, which then increases the overall amplitude and duration of T cell signaling. ![]() 2 MHC–TCR interaction. Structures for the extracellular portions of MHC–peptide complexes, TCRαβ modules and the trimolecular MHC–peptide–TCR complex, are known from X-ray crystallography 5. TCRδε and TCRγε modules form extracellular disulfide-linked immunoglobulin domains, but no high-resolution structures are available. Stoichiometries other than that shown have been proposed. The cytoplasmic domains of the δ, ε, γ and ζ subunits carry 1–3 copies of the characteristic immunoreceptor Tyr-based activation motif (ITAM, blue boxes) YxxLx 6–8YxxL. Tyr residues in these sequences are phosphorylated by membrane-associated kinases upon receptor engagement. The relatively large cytoplasmic domains of the ζζ module might form a membrane-associated helical structure involved in signal transduction 48. Abbreviations: MHC, major histocompatibility complex; TCR, T-cell antigen receptor. ![]() ![]() 3 Soluble oligomeric major histocompatibility complex (MHC)–peptide complexes for studying T-cell activation processes. (a–d)Schematic diagrams of various MHC oligomerization strategies. (e–i)Scale models of oligomer components. Colors are consistent for the various species throughout all panels. (e) Ribbon diagram of the MHC–peptide complex, with αβ subunits in green, and bound antigenic peptide shown in yellow. Flexible β-subunit connecting peptide region (eight residues) is shown in red. MHC oligomers have been made through attachments to the α or β subunit termini, with linkers of up to 12 residues. (f) Antibody (IgG) ribbon diagram with antigen-binding domain (F ab) in purple, constant (Fc) domain in orange and flexible hinge region in red. MHC–peptide dimers have been produced as IgG–MHC complexes (a) 17,18. (g) Ribbon diagram of antibody Fc domain, used to prepare chimeric Fc–MHC dimers (b) 19,20. (h) Streptavidin (SA) ribbon diagram (blue), with biotin-binding sites used to link biotinylated MHC–peptide complexes 21 shown as yellow circles. SA-linked MHC dimers, trimers and tetramers (c) have been produced by this method. The exact valency of such complexes can be difficult to determine, particularly for streptavidin–phycoerythrin conjugates, which are large aggregates 26. (i) Peptide-based synthetic tetrameric cross-linker (xlink) shown as a ball-and-stick model, with reactive maleimide groups used to attach MHC monomers indicated by arrows, and fluorescent probe indicated by asterisk. MHC dimers, trimers and tetramers (d) have been prepared by this strategy 23,24. All structural diagrams (e–i) are drawn to the same scale. Cell 73, 209-212. Wilson, D.B., Wilson, D.H., Schroder, K., Pinilla, C., Blondelle, S, Houghten, RA., and Garcia, KC. Specificity and degeneracy of T cells. Mol Immunol 40, 1047-1055. Wulfing, C., and Davis, M.M. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. (2002), Flow cytometry used for the analysis of calcium signaling induced by antigen-specific. T-cell receptor. Movement triggered by costimulation during T. T-cell activation by the B7 costimulatory pathway. In 1970 Bretscher and Cohn put forth the two-signal model of lymphocyte activation to explain self/nonself dis- crimination (1). This model proposes that T-cell activation requires two independent signals. The first is transduced through the T-cell receptor (TCR) after. ![]() The net inward movement of F. Complexes at the IS during early phases of T cell activation. Cytoskeletal remodeling in T cell receptor signaling. The CH27 cell is substantially larger than the T cells. The T cell intracellular calcium concentration is overlaid in a false color scale from blue (low concentration) to red (high concentration) to mark the onset of T cell activation, set to time 0:00 min. Although the beads, one of which is marked with an arrow, are bound to the. ![]() Arrows indicate attachment points. 4 Large-scale membrane rearrangements during T-cell activation. (a) Fluorescent microscopy of interaction between a T cell and a supported bilayer carrying labeled MHC–peptide complexes (green) and ICAM adhesion molecules (red). The view is normal to the membrane interface. Image adapted with permission from Grakoui et al. 33 © 1999 American Association for the Advancement of Science. (b) Schematic diagram of molecular interactions at the immunological synapse. MHC–peptide complexes and TCRs cluster in the center, and are surrounded by adhesion molecules such as ICAM and LFA-1. Video microscopy movies available on the web include: formation of the immunological synapse 33 (), cytoskeletal movements and the synapse 49 () and differential clustering of CD3 and CD4 (Ref. Abbreviations: MHC, major histocompatibility complex; TCR, T-cell antigen receptor.
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