Abstract
Many antigen receptors of the immune system belong to the family of multichain immune recognition receptors (MIRRs). Binding of ligand (antigen) to MIRR results in receptor phosphorylation, triggering downstream signaling pathways and cellular activation. How ligand binding induces this phosphorylation is not yet understood. In this Chapter, we discuss two models exploring the possibihty that kinases and phosphatases are intermingled on the cell surface. Thus, in resting state, MIRR phosphorylation is counteracted by dephosphorylation. Upon ligand binding, phosphatases are removed from the vicinity of the MIRR and kinases, such that phosphorylated MIRRs can accumulate (segregation models). In the first model, clustering of MIRRs by multivalent hgand leads to their concentration in lipid rafts where kinases, but not phosphatases, are localized. The second model takes into account that the MIRR-ligand pair needs close apposition of the two cell membranes, in cases where ligand is presented by an antigen-presenting cell. The intermembrane distance is too small to accommodate transmembrane phosphatases, which possess large ectodomains. Thus, phosphatases become spatially separated from the MIRRs and kinases (kinetic-segregation model).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Reth M. Antigen receptor tail clue. Nature 1989; 338:383.
Iwashima M, Irving BA, van Oers NS et al. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 1994; 263(5150):1136–1139.
Rolli V, Gallwitz M, Wossning T et al. Amplification of B-cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol Cell 2002; 10(5): 1057–1069.
Gil D, Schamel WW, Montoya M et al. Recruitment of Nek by CD3 epsilon reveals a ligand-induced conformational change essential for T-cell receptor signaling and synapse formation. Cell 2002; 109(7):901–912.
Schamel WW, Risueno RM, Minguet S et al. A conformation-and avidity-based proofreading mechanism for the TCR-CD3 complex. Trends Immunol 2006; 27:176–182.
Cochran JR, Aivazian D, Cameron TO et al. Receptor clustering and transmembrane signaling in Tcells. Trends Biochem Sci 2001; 26(5):304–310.
Secrist JP, Burns LA, Karnitz L et al. Stimulatory effects of the protein tyrosine phosphatase inhibitor, pervanadate, on T-cell activation events. J Biol Chem 1993; 268(8):5886–5893.
Wienands J, Larbolette O, Reth M. Evidence for a preformed transducer complex organized by the B-ceil antigen receptor. Proc Nad Acad Sci USA 1996; 93(15):7865–7870.
Cooper JA, MacAuley A. Potential positive and negative autoregulation of p60c-src by intermolecular autophosphorylation. Proc Nad Acad Sci USA 1988; 85(12):4232–4236.
Trowbridge IS, Thomas ML. CD45: An emerging role as a protein tyrosine phosphatase required ft)r lymphocyte activation and development. Annu Rev Immunol 1994; 12:85–116.
Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol 2002; 3(12):1129–1134.
Davis SJ, van der Merwe PA. The structure and ligand interactions of CD2: Implications ft)r T-cell function. Immunol Today 1996; 17(4): 177–187.
Shaw AS, Dustin ML. Making the T-cell receptor go the distance: A topological view of T-cell activation. Immunity 1997; 6(4):361–369.
Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science 1972; 175(23):720–731.
Simons K, Ikonen E. Functional rafts in cell membranes. Nature 1997; 387(6633):569–572.
Wenk MR. The emerging field of lipidomics. Nat Rev Drug Discov 2005; 4(7):594–610.
Fridriksson EK, Shipkova PA, Sheets ED et al. Quantitative analysis of phospholipids in functionally important membrane domains from RBL-2H3 mast cells using tandem high-resolution mass spectrometry. Biochemistry 1999; 38(25):8056–8063.
Janes PW, Ley SC, Magee AL Aggregation of lipid rafts accompanies signaling via the T-cell antigen receptor. J Cell Biol 1999; 147(2):447–461.
Drevot P, Langlet C, Guo XJ et al. TCR signal initiation machinery is pre-assembled and activated in a subset of membrane rafts. EMBO J 2002; 21(8):1899–1908.
Xavier R, Brennan T, Li Q et al. Membrane compartmentation is required for efficient T-cell activation. Immunity 1998; 8:723–732.
Montixi C, Langlet C, Bernard AM et al. Engagement of T-cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J 1998; 17(18):5334–5348.
Field KA, Holowka D, Baird B. Compartmentalized activation of the high affinity immunoglobulin E receptor within membrane domains. J Biol Chem 1997; 272(7):4276–4280.
Cheng PC, Dykstra ML, Mitchell RN et al. A role for lipid rafts in B-cell antigen receptor signaling and antigen targeting. J Exp Med 1999; 190(11):1549–1560.
Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000; 1(1):31–39.
Langlet C, Bernard AM, Drevot P et al. Membrane rafts and signaling by the multichain immime recognition receptors. Curr Opin Immunol 2000; 12(3):250–255.
Kabouridis PS, Magee AI, Ley SC. S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T-lymphocytes. EMBO J 1997; 16(16):4983–4998.
Munro S. Lipid rafts:elusive or illusive? Cell 2003; 115(4):377–388.
Janes PW, Ley SC, Magee AI et al. The role of lipid rafts in T-cell antigen receptor (TCR) signalling. Semin Immunol 2000; 12(1):23–34.
Lanzavecchia A, Lezzi G, Viola A. From TCR engagement to T-cell activation: A kinetic view of T-cell behavior. Cell 1999; 96(1):1–4.
Garboczi DN, Ghosh P, Utz U et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 1996; 384(6605):134–141.
Garcia KC, Degano M, Stanfield RL et al. An a P T-cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 1996; 274(5285):209–219.
Davis SJ, van der Merwe PA. The kinetic-segregation model: TCR triggering and beyond. Nat Immunol 2006; 7(8):803–809.
Davis MM, Boniface JJ, Reich Z et al. Ligand recognition by a P T-cell receptors. Annu Rev Immunol1998; 16:523–544.
Yokosuka T, Sakata-Sogawa K, Kobayashi W et al. Newly generated T-cell receptor microclusters initiate and sustain T-cell activation by recruitment of Zap70 and SLP-76. Nat Immunol 2005; 6(12):1253–1262.
Lin J, Weiss A. The tyrosine phosphatase CD 148 is excluded from the immunologic synapse and down-regulates prolonged T-cell signaling. J Cell Biol 18 2003; 162(4):673–682.
Choudhuri K, Wiseman D, Brown MH et al. T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 2005; 436(7050):578–582.
Irles C, Symons A, Michel F et al. CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling. Nat Immunol 2003; 4(2):189–197.
Varma R, Campi G, Yokosuka T et al. T-cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 2006; 25(1):117–127.
Batista FD, Iber D, Neuberger MS. B-cells acquire antigen from target cells after synapse formation. Nature 2001; 411(6836):489–494.
Chang TW, Kung PC, Gingras SP et al. Does OKT3 monoclonal antibody react with an antigenrecognition structure on human T-cells? Proc Natl Acad Sci USA 1981; 78(3):1805–1808.
Kaye J, Janeway CA Jr. The Fab fragment of a directly activating monoclonal antibody that precipitates a disulfide-linked heterodimer from a helper T-cell clone blocks activation by either allogeneic la or antigen and self-la. J Exp Med 1984; 159(5):1397–1412.
Boniface JJ, Rabinowitz JD, Wiilfing C et al. Initiation of signal transduction through the T-cell receptor requires the peptide multivalent engagement of MHC ligands. Immimity 1998; 9:459–466.
Cochran JR, Cameron TO, Stern LJ. The relationship of MHC-peptide binding and T-cell activation probed using chemically defined MHC class II oligomers. Immunity 2000; 12(3):241–250.
Krogsgaard M, Li QJ, Sumen C et al. Agonist/endogenous peptide-MHC heterodimers drive T-cell activation and sensitivity. Nature 2005; 434(7030):238–243.
Monks CR, Freiberg BA, Kupfer H et al. Three-dimensional segregation of supramolecular activation clusters in T-cells. Nature 1998; 395(6697): 82–86.
Grakoui A, Bromley SK, Sumen C et al. The immunological synapse: A molecular machine controlling T-cell activation. Science 1999; 285(5425):221–227.
Carrasco YR, Batista FD. B-cell recognition of membrane-bound antigen: An exquisite way of sensing ligands. Curr Opin Immunol 2006; 18(3):286–291.
Lee KH, Holdorf AD, Dustin ML et al. T-cell receptor signaling precedes immunological synapse formation. Science 2002; 295(5559):1539–1542.
Freiberg BA, Kupfer H, Maslanik W et al. Staging and resetting T-cell activation in SMACs. Nat Immunol 2002; 3(10):911–917.
Lee KH, Dinner AR, Tu C et al. The immunological synapse balances T-cell receptor signaling and degradation. Science 2003; 302(5648): 1218–1222.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Dopfer, E.P., Swamy, M., Siegers, G.M., Molnar, E., Yang, J., Schamel, W.W.A. (2008). Segregation Models. In: Sigalov, A.B. (eds) Multichain Immune Recognition Receptor Signaling. Advances in Experimental Medicine and Biology, vol 640. Springer, New York, NY. https://doi.org/10.1007/978-0-387-09789-3_7
Download citation
DOI: https://doi.org/10.1007/978-0-387-09789-3_7
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-09788-6
Online ISBN: 978-0-387-09789-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)