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Molecular mechanisms and functional implications of polarized actin remodeling at the T cell immunological synapse

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Abstract

Transient,specialized cell–cell interactions play a central role in leukocyte function by enabling specific intercellular communication in the context of a highly dynamic systems level response. The dramatic structural changes required for the formation of these contacts are driven by rapid and precise cytoskeletal remodeling events. In recent years, the immunological synapse that forms between a T lymphocyte and its antigen-presenting target cell has emerged as an important model system for understanding immune cell interactions. In this review, we discuss how regulators of the cortical actin cytoskeleton control synaptic architecture and in this way specify T cell function.

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References

  1. Dustin ML, Chakraborty AK, Shaw AS (2010) Understanding the structure and function of the immunological synapse. Cold Spring Harb Perspect Biol 2(10):a002311. doi:10.1101/cshperspect.a002311

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Harwood NE, Batista FD (2010) Early events in B cell activation. Annu Rev Immunol 28:185–210

    CAS  PubMed  Google Scholar 

  3. Dustin ML, Long EO (2010) Cytotoxic immunological synapses. Immunol Rev 235(1):24–34. doi:10.1111/j.0105-2896.2010.00904.x

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Gomez TS, Billadeau DD (2008) T cell activation and the cytoskeleton: you can’t have one without the other. Adv Immunol 97:1–64

    CAS  PubMed  Google Scholar 

  5. Yi J, Wu XS, Crites T, Hammer JA 3rd (2012) Actin retrograde flow and actomyosin II arc contraction drive receptor cluster dynamics at the immunological synapse in Jurkat T cells. Mol Biol Cell 23(5):834–852. doi:10.1091/mbc.E11-08-0731

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Brown AC, Oddos S, Dobbie IM, Alakoskela JM, Parton RM, Eissmann P, Neil MA, Dunsby C, French PM, Davis I, Davis DM (2011) Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy. PLoS Biol 9(9):e1001152. doi:10.1371/journal.pbio.1001152

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Rak GD, Mace EM, Banerjee PP, Svitkina T, Orange JS (2011) Natural killer cell lytic granule secretion occurs through a pervasive actin network at the immune synapse. PLoS Biol 9(9):e1001151. doi:10.1371/journal.pbio.1001151

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Stinchcombe JC, Majorovits E, Bossi G, Fuller S, Griffiths GM (2006) Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443(7110):462–465

    CAS  PubMed  Google Scholar 

  9. Huse M, Quann EJ, Davis MM (2008) Shouts, whispers, and the kiss of death: directional secretion in T cells. Nat Immunol 9(10):1105–1111

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Stinchcombe JC, Griffiths GM (2007) Secretory mechanisms in cell-mediated cytotoxicity. Annu Rev Cell Dev Biol 23:495–517

    CAS  PubMed  Google Scholar 

  11. Balagopalan L, Sherman E, Barr VA, Samelson LE (2011) Imaging techniques for assaying lymphocyte activation in action. Nat Rev 11(1):21–33. doi:10.1038/nri2903

    CAS  Google Scholar 

  12. Groves JT, Dustin ML (2003) Supported planar bilayers in studies on immune cell adhesion and communication. J Immunol Methods 278(1–2):19–32

    CAS  PubMed  Google Scholar 

  13. Schneckenburger H (2005) Total internal reflection fluorescence microscopy: technical innovations and novel applications. Curr Opin Biotechnol 16(1):13–18

    CAS  PubMed  Google Scholar 

  14. Sherman E, Barr V, Manley S, Patterson G, Balagopalan L, Akpan I, Regan CK, Merrill RK, Sommers CL, Lippincott-Schwartz J, Samelson LE (2011) Functional nanoscale organization of signaling molecules downstream of the T cell antigen receptor. Immunity 35(5):705–720. doi:10.1016/j.immuni.2011.10.004

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Williamson DJ, Owen DM, Rossy J, Magenau A, Wehrmann M, Gooding JJ, Gaus K (2011) Pre-existing clusters of the adaptor Lat do not participate in early T cell signaling events. Nat Immunol 12(7):655–662. doi:10.1038/ni.2049

    CAS  PubMed  Google Scholar 

  16. Lillemeier BF, Mortelmaier MA, Forstner MB, Huppa JB, Groves JT, Davis MM (2009) TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat Immunol 11(1):90–96

    PubMed Central  PubMed  Google Scholar 

  17. Huse M, Klein LO, Girvin AT, Faraj JM, Li QJ, Kuhns MS, Davis MM (2007) Spatial and temporal dynamics of T cell receptor signaling with a photoactivatable agonist. Immunity 27(1):76–88

    CAS  PubMed  Google Scholar 

  18. Stinchcombe JC, Bossi G, Booth S, Griffiths GM (2001) The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15(5):751–761

    CAS  PubMed  Google Scholar 

  19. Ueda H, Morphew MK, McIntosh JR, Davis MM (2011) CD4+ T-cell synapses involve multiple distinct stages. Proc Natl Acad Sci USA 108(41):17099–17104. doi:10.1073/pnas.1113703108

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Boes M, Cerny J, Massol R, Op den Brouw M, Kirchhausen T, Chen J, Ploegh HL (2002) T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418(6901):983–988. doi:10.1038/nature01004

    CAS  PubMed  Google Scholar 

  21. Chow A, Toomre D, Garrett W, Mellman I (2002) Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418(6901):988–994. doi:10.1038/nature01006

    CAS  PubMed  Google Scholar 

  22. Pulecio J, Petrovic J, Prete F, Chiaruttini G, Lennon-Dumenil AM, Desdouets C, Gasman S, Burrone OR, Benvenuti F (2010) Cdc42-mediated MTOC polarization in dendritic cells controls targeted delivery of cytokines at the immune synapse. J Exp Med 207(12):2719–2732. doi:10.1084/jem.20100007

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Huse M (2009) The T-cell-receptor signaling network. J Cell Sci 122(Pt 9):1269–1273

    CAS  PubMed  Google Scholar 

  24. Derivery E, Gautreau A (2010) Generation of branched actin networks: assembly and regulation of the N-WASP and WAVE molecular machines. BioEssays 32(2):119–131. doi:10.1002/bies.200900123

    CAS  PubMed  Google Scholar 

  25. Goley ED, Welch MD (2006) The ARP2/3 complex: an actin nucleator comes of age. Nat Rev Mol Cell Biol 7(10):713–726. doi:10.1038/nrm2026

    CAS  PubMed  Google Scholar 

  26. Gomez TS, Kumar K, Medeiros RB, Shimizu Y, Leibson PJ, Billadeau DD (2007) Formins regulate the actin-related protein 2/3 complex-independent polarization of the centrosome to the immunological synapse. Immunity 26(2):177–190

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269

    CAS  PubMed  Google Scholar 

  28. Ramesh N, Geha R (2009) Recent advances in the biology of WASP and WIP. Immunol Res 44(1–3):99–111. doi:10.1007/s12026-008-8086-1

    PubMed  Google Scholar 

  29. Ku GM, Yablonski D, Manser E, Lim L, Weiss A (2001) A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT. EMBO J 20(3):457–465. doi:10.1093/emboj/20.3.457

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Sanui T, Inayoshi A, Noda M, Iwata E, Oike M, Sasazuki T, Fukui Y (2003) DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1. T cells. Immunity 19(1):119–129

    CAS  Google Scholar 

  31. Cannon JL, Labno CM, Bosco G, Seth A, McGavin MH, Siminovitch KA, Rosen MK, Burkhardt JK (2001) Wasp recruitment to the T cell:APC contact site occurs independently of Cdc42 activation. Immunity 15(2):249–259

    CAS  PubMed  Google Scholar 

  32. Higgs HN, Pollard TD (2000) Activation by Cdc42 and PIP(2) of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex. J Cell Biol 150(6):1311–1320

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner MW (1999) The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97(2):221–231

    CAS  PubMed  Google Scholar 

  34. Ochs HD (1998) The Wiskott-Aldrich syndrome. Semin Hematol 35(4):332–345

    CAS  PubMed  Google Scholar 

  35. Molina IJ, Sancho J, Terhorst C, Rosen FS, Remold-O’Donnell E (1993) T cells of patients with the Wiskott-Aldrich syndrome have a restricted defect in proliferative responses. J Immunol 151(8):4383–4390

    CAS  PubMed  Google Scholar 

  36. Trifari S, Sitia G, Aiuti A, Scaramuzza S, Marangoni F, Guidotti LG, Martino S, Saracco P, Notarangelo LD, Roncarolo MG, Dupre L (2006) Defective Th1 cytokine gene transcription in CD4+ and CD8+ T cells from Wiskott-Aldrich syndrome patients. J Immunol 177(10):7451–7461

    CAS  PubMed  Google Scholar 

  37. Barda-Saad M, Shirasu N, Pauker MH, Hassan N, Perl O, Balbo A, Yamaguchi H, Houtman JC, Appella E, Schuck P, Samelson LE (2010) Cooperative interactions at the SLP-76 complex are critical for actin polymerization. EMBO J 29(14):2315–2328. doi:10.1038/emboj.2010.133

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Tybulewicz VL (2005) Vav-family proteins in T-cell signalling. Curr Opin Immunol 17(3):267–274

    CAS  PubMed  Google Scholar 

  39. Zhang J, Shehabeldin A, da Cruz LA, Butler J, Somani AK, McGavin M, Kozieradzki I, dos Santos AO, Nagy A, Grinstein S, Penninger JM, Siminovitch KA (1999) Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J Exp Med 190(9):1329–1342

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Gallego MD, Santamaria M, Pena J, Molina IJ (1997) Defective actin reorganization and polymerization of Wiskott-Aldrich T cells in response to CD3-mediated stimulation. Blood 90(8):3089–3097

    CAS  PubMed  Google Scholar 

  41. Calvez R, Lafouresse F, De Meester J, Galy A, Valitutti S, Dupre L (2011) The Wiskott-Aldrich syndrome protein permits assembly of a focused immunological synapse enabling sustained T-cell receptor signaling. Haematologica 96(10):1415–1423. doi:10.3324/haematol.2011.040204

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Kenney D, Cairns L, Remold-O’Donnell E, Peterson J, Rosen FS, Parkman R (1986) Morphological abnormalities in the lymphocytes of patients with the Wiskott-Aldrich syndrome. Blood 68(6):1329–1332

    CAS  PubMed  Google Scholar 

  43. Cannon JL, Burkhardt JK (2004) Differential roles for Wiskott-Aldrich syndrome protein in immune synapse formation and IL-2 production. J Immunol 173(3):1658–1662

    CAS  PubMed  Google Scholar 

  44. Krawczyk C, Oliveira-dos-Santos A, Sasaki T, Griffiths E, Ohashi PS, Snapper S, Alt F, Penninger JM (2002) Vav1 controls integrin clustering and MHC/peptide-specific cell adhesion to antigen-presenting cells. Immunity 16(3):331–343

    CAS  PubMed  Google Scholar 

  45. Sims TN, Soos TJ, Xenias HS, Dubin-Thaler B, Hofman JM, Waite JC, Cameron TO, Thomas VK, Varma R, Wiggins CH, Sheetz MP, Littman DR, Dustin ML (2007) Opposing effects of PKCtheta and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129(4):773–785

    CAS  PubMed  Google Scholar 

  46. Chemin K, Bohineust A, Dogniaux S, Tourret M, Guegan S, Miro F, Hivroz C (2012) Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J Immunol 189(5):2159–2168. doi:10.4049/jimmunol.1200156

    CAS  PubMed  Google Scholar 

  47. Dustin ML (2007) Cell adhesion molecules and actin cytoskeleton at immune synapses and kinapses. Curr Opin Cell Biol 19(5):529–533. doi:10.1016/j.ceb.2007.08.003

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Nolz JC, Gomez TS, Zhu P, Li S, Medeiros RB, Shimizu Y, Burkhardt JK, Freedman BD, Billadeau DD (2006) The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr Biol 16(1):24–34

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Le Floc’h A, Tanaka Y, Bantilan NS, Voisinne G, Altan-Bonnet G, Fukui Y, Huse M (2013) Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse. J Exp Med 210(12):2721–2737. doi:10.1084/jem.20131324

    PubMed Central  PubMed  Google Scholar 

  50. Yu H, Leitenberg D, Li B, Flavell RA (2001) Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 194(7):915–926

    CAS  PubMed Central  PubMed  Google Scholar 

  51. de la Roche M, Ritter AT, Angus KL, Dinsmore C, Earnshaw CH, Reiter JF, Griffiths GM (2013) Hedgehog signaling controls T cell killing at the immunological synapse. Science 342(6163):1247–1250. doi:10.1126/science.1244689

    PubMed Central  PubMed  Google Scholar 

  52. Hao JJ, Zhu J, Zhou K, Smith N, Zhan X (2005) The coiled-coil domain is required for HS1 to bind to F-actin and activate Arp2/3 complex. J Biol Chem 280(45):37988–37994. doi:10.1074/jbc.M504552200

    CAS  PubMed  Google Scholar 

  53. Gomez TS, McCarney SD, Carrizosa E, Labno CM, Comiskey EO, Nolz JC, Zhu P, Freedman BD, Clark MR, Rawlings DJ, Billadeau DD, Burkhardt JK (2006) HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse. Immunity 24(6):741–752

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Carrizosa E, Gomez TS, Labno CM, Klos Dehring DA, Liu X, Freedman BD, Billadeau DD, Burkhardt JK (2009) Hematopoietic lineage cell-specific protein 1 is recruited to the immunological synapse by IL-2-inducible T cell kinase and regulates phospholipase Cgamma1 Microcluster dynamics during T cell spreading. J Immunol 183(11):7352–7361. doi:10.4049/jimmunol.0900973

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Dehring DA, Clarke F, Ricart BG, Huang Y, Gomez TS, Williamson EK, Hammer DA, Billadeau DD, Argon Y, Burkhardt JK (2011) Hematopoietic lineage cell-specific protein 1 functions in concert with the Wiskott-Aldrich syndrome protein to promote podosome array organization and chemotaxis in dendritic cells. J Immunol 186(8):4805–4818. doi:10.4049/jimmunol.1003102

    PubMed Central  PubMed  Google Scholar 

  56. Rossman KL, Der CJ, Sondek J (2005) GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6(2):167–180. doi:10.1038/nrm1587

    CAS  PubMed  Google Scholar 

  57. Zeng R, Cannon JL, Abraham RT, Way M, Billadeau DD, Bubeck-Wardenberg J, Burkhardt JK (2003) SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site. J Immunol 171(3):1360–1368

    CAS  PubMed  Google Scholar 

  58. Ardouin L, Bracke M, Mathiot A, Pagakis SN, Norton T, Hogg N, Tybulewicz VL (2003) Vav1 transduces TCR signals required for LFA-1 function and cell polarization at the immunological synapse. Eur J Immunol 33(3):790–797

    CAS  PubMed  Google Scholar 

  59. Fischer KD, Kong YY, Nishina H, Tedford K, Marengere LE, Kozieradzki I, Sasaki T, Starr M, Chan G, Gardener S, Nghiem MP, Bouchard D, Barbacid M, Bernstein A, Penninger JM (1998) Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Curr Biol 8(10):554–562

    CAS  PubMed  Google Scholar 

  60. Holsinger LJ, Graef IA, Swat W, Chi T, Bautista DM, Davidson L, Lewis RS, Alt FW, Crabtree GR (1998) Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction. Curr Biol 8(10):563–572

    CAS  PubMed  Google Scholar 

  61. Wulfing C, Bauch A, Crabtree GR, Davis MM (2000) The vav exchange factor is an essential regulator in actin-dependent receptor translocation to the lymphocyte-antigen-presenting cell interface. Proc Natl Acad Sci USA 97(18):10150–10155

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Reynolds LF, de Bettignies C, Norton T, Beeser A, Chernoff J, Tybulewicz VL (2004) Vav1 transduces T cell receptor signals to the activation of the Ras/ERK pathway via LAT, Sos, and RasGRP1. J Biol Chem 279(18):18239–18246. doi:10.1074/jbc.M400257200

    CAS  PubMed  Google Scholar 

  63. Reynolds LF, Smyth LA, Norton T, Freshney N, Downward J, Kioussis D, Tybulewicz VL (2002) Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways. J Exp Med 195(9):1103–1114

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Faure S, Salazar-Fontana LI, Semichon M, Tybulewicz VL, Bismuth G, Trautmann A, Germain RN, Delon J (2004) ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat Immunol 5(3):272–279. doi:10.1038/ni1039

    CAS  PubMed  Google Scholar 

  65. Bretscher A, Edwards K, Fehon RG (2002) ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3(8):586–599. doi:10.1038/nrm882

    CAS  PubMed  Google Scholar 

  66. Miletic AV, Graham DB, Sakata-Sogawa K, Hiroshima M, Hamann MJ, Cemerski S, Kloeppel T, Billadeau DD, Kanagawa O, Tokunaga M, Swat W (2009) Vav links the T cell antigen receptor to the actin cytoskeleton and T cell activation independently of intrinsic Guanine nucleotide exchange activity. PLoS ONE 4(8):e6599. doi:10.1371/journal.pone.0006599

    PubMed Central  PubMed  Google Scholar 

  67. Cote JF, Vuori K (2007) GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol 17(8):383–393. doi:10.1016/j.tcb.2007.05.001

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Nishikimi A, Kukimoto-Niino M, Yokoyama S, Fukui Y (2013) Immune regulatory functions of DOCK family proteins in health and disease. Exp Cell Res 319(15):2343–2349. doi:10.1016/j.yexcr.2013.07.024

    CAS  PubMed  Google Scholar 

  69. Kunisaki Y, Nishikimi A, Tanaka Y, Takii R, Noda M, Inayoshi A, Watanabe K, Sanematsu F, Sasazuki T, Sasaki T, Fukui Y (2006) DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. J Cell Biol 174(5):647–652. doi:10.1083/jcb.200602142

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Nishikimi A, Fukuhara H, Su W, Hongu T, Takasuga S, Mihara H, Cao Q, Sanematsu F, Kanai M, Hasegawa H, Tanaka Y, Shibasaki M, Kanaho Y, Sasaki T, Frohman MA, Fukui Y (2009) Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis. Science 324(5925):384–387. doi:10.1126/science.1170179

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Fukui Y, Hashimoto O, Sanui T, Oono T, Koga H, Abe M, Inayoshi A, Noda M, Oike M, Shirai T, Sasazuki T (2001) Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412(6849):826–831. doi:10.1038/35090591

    CAS  PubMed  Google Scholar 

  72. Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, Megias D, Marques M, Carrera AC, Manes S, Fukui Y, Martinez AC, Stein JV (2004) Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing. Immunity 21(3):429–441. doi:10.1016/j.immuni.2004.07.012

    CAS  PubMed  Google Scholar 

  73. Ham H, Guerrier S, Kim J, Schoon RA, Anderson EL, Hamann MJ, Lou Z, Billadeau DD (2013) Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity. J Immunol 190(7):3661–3669. doi:10.4049/jimmunol.1202792

    CAS  PubMed  Google Scholar 

  74. Randall KL, Chan SS, Ma CS, Fung I, Mei Y, Yabas M, Tan A, Arkwright PD, Al Suwairi W, Lugo Reyes SO, Yamazaki-Nakashimada MA, Garcia-Cruz Mde L, Smart JM, Picard C, Okada S, Jouanguy E, Casanova JL, Lambe T, Cornall RJ, Russell S, Oliaro J, Tangye SG, Bertram EM, Goodnow CC (2011) DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J Exp Med 208(11):2305–2320. doi:10.1084/jem.20110345

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Randall KL, Lambe T, Goodnow CC, Cornall RJ (2010) The essential role of DOCK8 in humoral immunity. Dis Markers 29(3–4):141–150. doi:10.3233/DMA-2010-0739

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Randall KL, Lambe T, Johnson AL, Treanor B, Kucharska E, Domaschenz H, Whittle B, Tze LE, Enders A, Crockford TL, Bouriez-Jones T, Alston D, Cyster JG, Lenardo MJ, Mackay F, Deenick EK, Tangye SG, Chan TD, Camidge T, Brink R, Vinuesa CG, Batista FD, Cornall RJ, Goodnow CC (2009) Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat Immunol 10(12):1283–1291. doi:10.1038/ni.1820

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, Chen A, Kim HS, Lloret MG, Schulze I, Ehl S, Thiel J, Pfeifer D, Veelken H, Niehues T, Siepermann K, Weinspach S, Reisli I, Keles S, Genel F, Kutukculer N, Camcioglu Y, Somer A, Karakoc-Aydiner E, Barlan I, Gennery A, Metin A, Degerliyurt A, Pietrogrande MC, Yeganeh M, Baz Z, Al-Tamemi S, Klein C, Puck JM, Holland SM, McCabe ER, Grimbacher B, Chatila TA (2009) Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 124(6):1289–1302. doi:10.1016/j.jaci.2009.10.038

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, Matthews HF, Davis J, Turner ML, Uzel G, Holland SM, Su HC (2009) Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 361(21):2046–2055. doi:10.1056/NEJMoa0905506

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, Longworth SA, Vinup KE, Mrass P, Oliaro J, Killeen N, Orange JS, Russell SM, Weninger W, Reiner SL (2007) Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315(5819):1687–1691

    CAS  PubMed  Google Scholar 

  80. Thaunat O, Granja AG, Barral P, Filby A, Montaner B, Collinson L, Martinez-Martin N, Harwood NE, Bruckbauer A, Batista FD (2012) Asymmetric segregation of polarized antigen on B cell division shapes presentation capacity. Science 335(6067):475–479. doi:10.1126/science.1214100

    CAS  PubMed  Google Scholar 

  81. Teixeiro E, Daniels MA, Hamilton SE, Schrum AG, Bragado R, Jameson SC, Palmer E (2009) Different T cell receptor signals determine CD8+ memory versus effector development. Science 323(5913):502–505. doi:10.1126/science.1163612

    CAS  PubMed  Google Scholar 

  82. Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock D, Manis J, Keles S, Ceja R, Chatila TA, Geha RS (2012) DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol 13(6):612–620. doi:10.1038/ni.2305

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Sakai Y, Tanaka Y, Yanagihara T, Watanabe M, Duan X, Terasawa M, Nishikimi A, Sanematsu F, Fukui Y (2013) The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation. Blood 122(3):386–393. doi:10.1182/blood-2012-12-475897

    CAS  PubMed  Google Scholar 

  84. Costello PS, Gallagher M, Cantrell DA (2002) Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat Immunol 3(11):1082–1089. doi:10.1038/ni848

    CAS  PubMed  Google Scholar 

  85. Garcon F, Patton DT, Emery JL, Hirsch E, Rottapel R, Sasaki T, Okkenhaug K (2008) CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 111(3):1464–1471. doi:10.1182/blood-2007-08-108050

    CAS  PubMed  Google Scholar 

  86. Harriague J, Bismuth G (2002) Imaging antigen-induced PI3K activation in T cells. Nat Immunol 3(11):1090–1096

    CAS  PubMed  Google Scholar 

  87. Huppa JB, Gleimer M, Sumen C, Davis MM (2003) Continuous T cell receptor signaling required for synapse maintenance and full effector potential. Nat Immunol 4(8):749–755

    CAS  PubMed  Google Scholar 

  88. Fruman DA, Bismuth G (2009) Fine tuning the immune response with PI3 K. Immunol Rev 228(1):253–272. doi:10.1111/j.1600-065X.2008.00750.x

    CAS  PubMed  Google Scholar 

  89. Kok K, Nock GE, Verrall EA, Mitchell MP, Hommes DW, Peppelenbosch MP, Vanhaesebroeck B (2009) Regulation of p110delta PI 3-kinase gene expression. PLoS ONE 4(4):e5145. doi:10.1371/journal.pone.0005145

    PubMed Central  PubMed  Google Scholar 

  90. Okkenhaug K, Ali K, Vanhaesebroeck B (2007) Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K. Trends Immunol 28(2):80–87

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297(5583):1031–1034. doi:10.1126/science.10735601073560

    CAS  PubMed  Google Scholar 

  92. Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B (2006) The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 177(8):5122–5128

    CAS  PubMed  Google Scholar 

  93. Alcazar I, Marques M, Kumar A, Hirsch E, Wymann M, Carrera AC, Barber DF (2007) Phosphoinositide 3-kinase gamma participates in T cell receptor-induced T cell activation. J Exp Med 204(12):2977–2987. doi:10.1084/jem.20070366

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E, Shokat KM, Fisher AG, Merkenschlager M (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 105(22):7797–7802. doi:10.1073/pnas.0800928105

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Funamoto S, Meili R, Lee S, Parry L, Firtel RA (2002) Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109(5):611–623

    CAS  PubMed  Google Scholar 

  96. Iijima M, Devreotes P (2002) Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109(5):599–610

    CAS  PubMed  Google Scholar 

  97. Wang F, Herzmark P, Weiner OD, Srinivasan S, Servant G, Bourne HR (2002) Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils. Nat Cell Biol 4(7):513–518. doi:10.1038/ncb810

    CAS  PubMed  Google Scholar 

  98. Molon B, Gri G, Bettella M, Gomez-Mouton C, Lanzavecchia A, Martinez AC, Manes S, Viola A (2005) T cell costimulation by chemokine receptors. Nat Immunol 6(5):465–471. doi:10.1038/ni1191

    CAS  PubMed  Google Scholar 

  99. Bromley SK, Peterson DA, Gunn MD, Dustin ML (2000) Cutting edge: hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation. J Immunol 165(1):15–19

    CAS  PubMed  Google Scholar 

  100. Saito T, Yokosuka T (2006) Immunological synapse and microclusters: the site for recognition and activation of T cells. Curr Opin Immunol 18(3):305–313

    CAS  PubMed  Google Scholar 

  101. Varma R, Campi G, Yokosuka T, Saito T, Dustin ML (2006) T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25(1):117–127

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Shim EK, Jung SH, Lee JR (2011) Role of two adaptor molecules SLP-76 and LAT in the PI3K signaling pathway in activated T cells. J Immunol 186(5):2926–2935. doi:10.4049/jimmunol.1001785

    CAS  PubMed  Google Scholar 

  103. Shim EK, Moon CS, Lee GY, Ha YJ, Chae SK, Lee JR (2004) Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase. FEBS Lett 575(1–3):35–40. doi:10.1016/j.febslet.2004.07.090

    CAS  PubMed  Google Scholar 

  104. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE (1998) LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92(1):83–92

    CAS  PubMed  Google Scholar 

  105. Carpenter CL, Auger KR, Chanudhuri M, Yoakim M, Schaffhausen B, Shoelson S, Cantley LC (1993) Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem 268(13):9478–9483

    CAS  PubMed  Google Scholar 

  106. Holt KH, Olson L, Moye-Rowley WS, Pessin JE (1994) Phosphatidylinositol 3-kinase activation is mediated by high-affinity interactions between distinct domains within the p110 and p85 subunits. Mol Cell Biol 14(1):42–49

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370(6490):527–532

    CAS  PubMed  Google Scholar 

  108. Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J (1996) Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J 15(10):2442–2451

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Jimenez C, Hernandez C, Pimentel B, Carrera AC (2002) The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras. J Biol Chem 277(44):41556–41562. doi:10.1074/jbc.M205893200

    CAS  PubMed  Google Scholar 

  110. Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, Nye E, Stamp G, Alitalo K, Downward J (2007) Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129(5):957–968. doi:10.1016/j.cell.2007.03.051

    CAS  PubMed  Google Scholar 

  111. Suire S, Condliffe AM, Ferguson GJ, Ellson CD, Guillou H, Davidson K, Welch H, Coadwell J, Turner M, Chilvers ER, Hawkins PT, Stephens L (2006) Gbetagammas and the Ras binding domain of p110gamma are both important regulators of PI(3)Kgamma signalling in neutrophils. Nat Cell Biol 8(11):1303–1309. doi:10.1038/ncb1494

    CAS  PubMed  Google Scholar 

  112. Mor A, Philips MR (2006) Compartmentalized Ras/MAPK signaling. Annu Rev Immunol 24:771–800. doi:10.1146/annurev.immunol.24.021605.090723

    CAS  PubMed  Google Scholar 

  113. Genot E, Cantrell DA (2000) Ras regulation and function in lymphocytes. Curr Opin Immunol 12(3):289–294

    CAS  PubMed  Google Scholar 

  114. Mor A, Campi G, Du G, Zheng Y, Foster DA, Dustin ML, Philips MR (2007) The lymphocyte function-associated antigen-1 receptor costimulates plasma membrane Ras via phospholipase D2. Nat Cell Biol 9(6):713–719

    CAS  PubMed  Google Scholar 

  115. Jun JE, Rubio I, Roose JP (2013) Regulation of Ras exchange factors and cellular localization of Ras activation by lipid messengers in T cells. Front Immunol 4:239. doi:10.3389/fimmu.2013.00239

    PubMed Central  PubMed  Google Scholar 

  116. Samstag Y, Bader A, Meuer SC (1991) A serine phosphatase is involved in CD2-mediated activation of human T lymphocytes and natural killer cells. J Immunol 147(3):788–794

    CAS  PubMed  Google Scholar 

  117. Samstag Y, Eckerskorn C, Wesselborg S, Henning S, Wallich R, Meuer SC (1994) Costimulatory signals for human T-cell activation induce nuclear translocation of pp19/cofilin. Proc Natl Acad Sci USA 91(10):4494–4498

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Agnew BJ, Minamide LS, Bamburg JR (1995) Reactivation of phosphorylated actin depolymerizing factor and identification of the regulatory site. J Biol Chem 270(29):17582–17587

    CAS  PubMed  Google Scholar 

  119. Moriyama K, Iida K, Yahara I (1996) Phosphorylation of Ser-3 of cofilin regulates its essential function on actin. Genes Cells 1(1):73–86

    CAS  PubMed  Google Scholar 

  120. Samstag Y, John I, Wabnitz GH (2013) Cofilin: a redox sensitive mediator of actin dynamics during T-cell activation and migration. Immunol Rev 256(1):30–47. doi:10.1111/imr.12115

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Eibert SM, Lee KH, Pipkorn R, Sester U, Wabnitz GH, Giese T, Meuer SC, Samstag Y (2004) Cofilin peptide homologs interfere with immunological synapse formation and T cell activation. Proc Natl Acad Sci USA 101(7):1957–1962. doi:10.1073/pnas.0308282100

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Freeman SA, Lei V, Dang-Lawson M, Mizuno K, Roskelley CD, Gold MR (2011) Cofilin-mediated F-actin severing is regulated by the Rap GTPase and controls the cytoskeletal dynamics that drive lymphocyte spreading and BCR microcluster formation. J Immunol 187(11):5887–5900. doi:10.4049/jimmunol.1102233

    CAS  PubMed  Google Scholar 

  123. Wabnitz GH, Nebl G, Klemke M, Schroder AJ, Samstag Y (2006) Phosphatidylinositol 3-kinase functions as a Ras effector in the signaling cascade that regulates dephosphorylation of the actin-remodeling protein cofilin after costimulation of untransformed human T lymphocytes. J Immunol 176(3):1668–1674

    CAS  PubMed  Google Scholar 

  124. Brieher WM, Kueh HY, Ballif BA, Mitchison TJ (2006) Rapid actin monomer-insensitive depolymerization of Listeria actin comet tails by cofilin, coronin, and Aip1. J Cell Biol 175(2):315–324. doi:10.1083/jcb.200603149

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Humphries CL, Balcer HI, D’Agostino JL, Winsor B, Drubin DG, Barnes G, Andrews BJ, Goode BL (2002) Direct regulation of Arp2/3 complex activity and function by the actin binding protein coronin. J Cell Biol 159(6):993–1004. doi:10.1083/jcb.200206113

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Kueh HY, Charras GT, Mitchison TJ, Brieher WM (2008) Actin disassembly by cofilin, coronin, and Aip1 occurs in bursts and is inhibited by barbed-end cappers. J Cell Biol 182(2):341–353. doi:10.1083/jcb.200801027

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Moshous D, Martin E, Carpentier W, Lim A, Callebaut I, Canioni D, Hauck F, Majewski J, Schwartzentruber J, Nitschke P, Sirvent N, Frange P, Picard C, Blanche S, Revy P, Fischer A, Latour S, Jabado N, de Villartay JP (2013) Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J Allergy Clin Immunol 131(6):1594–1603. doi:10.1016/j.jaci.2013.01.042

    CAS  PubMed  Google Scholar 

  128. Shiow LR, Paris K, Akana MC, Cyster JG, Sorensen RU, Puck JM (2009) Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin Immunol 131(1):24–30. doi:10.1016/j.clim.2008.11.002

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Shiow LR, Roadcap DW, Paris K, Watson SR, Grigorova IL, Lebet T, An J, Xu Y, Jenne CN, Foger N, Sorensen RU, Goodnow CC, Bear JE, Puck JM, Cyster JG (2008) The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immunol 9(11):1307–1315. doi:10.1038/ni.1662

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Foger N, Rangell L, Danilenko DM, Chan AC (2006) Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis. Science 313(5788):839–842. doi:10.1126/science.1130563

    PubMed  Google Scholar 

  131. Mueller P, Liu X, Pieters J (2011) Migration and homeostasis of naive T cells depends on coronin 1-mediated prosurvival signals and not on coronin 1-dependent filamentous actin modulation. J Immunol 186(7):4039–4050. doi:10.4049/jimmunol.1003352

    CAS  PubMed  Google Scholar 

  132. Mueller P, Massner J, Jayachandran R, Combaluzier B, Albrecht I, Gatfield J, Blum C, Ceredig R, Rodewald HR, Rolink AG, Pieters J (2008) Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering. Nat Immunol 9(4):424–431. doi:10.1038/ni1570

    CAS  PubMed  Google Scholar 

  133. Mugnier B, Nal B, Verthuy C, Boyer C, Lam D, Chasson L, Nieoullon V, Chazal G, Guo XJ, He HT, Rueff-Juy D, Alcover A, Ferrier P (2008) Coronin-1A links cytoskeleton dynamics to TCR alpha beta-induced cell signaling. PLoS ONE 3(10):e3467. doi:10.1371/journal.pone.0003467

    PubMed Central  PubMed  Google Scholar 

  134. Mace EM, Orange JS (2014) Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A. Proc Natl Acad Sci USA 111(18):6708–6713. doi:10.1073/pnas.1314975111

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Wabnitz GH, Lohneis P, Kirchgessner H, Jahraus B, Gottwald S, Konstandin M, Klemke M, Samstag Y (2010) Sustained LFA-1 cluster formation in the immune synapse requires the combined activities of L-plastin and calmodulin. Eur J Immunol 40(9):2437–2449. doi:10.1002/eji.201040345

    CAS  PubMed  Google Scholar 

  136. Wang C, Morley SC, Donermeyer D, Peng I, Lee WP, Devoss J, Danilenko DM, Lin Z, Zhang J, Zhou J, Allen PM, Brown EJ (2010) Actin-bundling protein L-plastin regulates T cell activation. J Immunol 185(12):7487–7497. doi:10.4049/jimmunol.1001424

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Morley SC (2013) The actin-bundling protein L-plastin supports T-cell motility and activation. Immunol Rev 256(1):48–62. doi:10.1111/imr.12102

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Le Goff E, Vallentin A, Harmand PO, Aldrian-Herrada G, Rebiere B, Roy C, Benyamin Y, Lebart MC (2010) Characterization of L-plastin interaction with beta integrin and its regulation by micro-calpain. Cytoskeleton 67(5):286–296. doi:10.1002/cm.20442

    PubMed  Google Scholar 

  139. Janji B, Giganti A, De Corte V, Catillon M, Bruyneel E, Lentz D, Plastino J, Gettemans J, Friederich E (2006) Phosphorylation on Ser5 increases the F-actin-binding activity of L-plastin and promotes its targeting to sites of actin assembly in cells. J Cell Sci 119(Pt 9):1947–1960. doi:10.1242/jcs.02874

    CAS  PubMed  Google Scholar 

  140. Gardel ML, Schneider IC, Aratyn-Schaus Y, Waterman CM (2010) Mechanical integration of actin and adhesion dynamics in cell migration. Annu Rev Cell Dev Biol 26:315–333. doi:10.1146/annurev.cellbio.011209.122036

    CAS  PubMed  Google Scholar 

  141. Wilson CA, Tsuchida MA, Allen GM, Barnhart EL, Applegate KT, Yam PT, Ji L, Keren K, Danuser G, Theriot JA (2010) Myosin II contributes to cell-scale actin network treadmilling through network disassembly. Nature 465(7296):373–377. doi:10.1038/nature08994

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Ilani T, Vasiliver-Shamis G, Vardhana S, Bretscher A, Dustin ML (2009) T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Nat Immunol 10(5):531–539. doi:10.1038/ni.1723

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Babich A, Li S, O’Connor RS, Milone MC, Freedman BD, Burkhardt JK (2012) F-actin polymerization and retrograde flow drive sustained PLCgamma1 signaling during T cell activation. J Cell Biol 197(6):775–787. doi:10.1083/jcb.201201018

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Jacobelli J, Chmura SA, Buxton DB, Davis MM, Krummel MF (2004) A single class II myosin modulates T cell motility and stopping, but not synapse formation. Nat Immunol 5(5):531–538. doi:10.1038/ni1065

    CAS  PubMed  Google Scholar 

  145. Hammer JA 3rd, Burkhardt JK (2013) Controversy and consensus regarding myosin II function at the immunological synapse. Curr Opin Immunol. doi:10.1016/j.coi.2013.03.010

    PubMed Central  PubMed  Google Scholar 

  146. Liu X, Kapoor TM, Chen JK, Huse M (2013) Diacylglycerol promotes centrosome polarization in T cells via reciprocal localization of dynein and myosin II. Proc Natl Acad Sci USA 110(29):11976–11981. doi:10.1073/pnas.1306180110

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Huse M, Le Floc’h A, Liu X (2013) From lipid second messengers to molecular motors: microtubule-organizing center reorientation in T cells. Immunol Rev 256(1):95–106. doi:10.1111/imr.12116

    CAS  PubMed  Google Scholar 

  148. Huse M (2012) Microtubule-organizing center polarity and the immunological synapse: protein kinase C and beyond. Front Immunol 3:235

  149. Sedwick CE, Morgan MM, Jusino L, Cannon JL, Miller J, Burkhardt JK (1999) TCR, LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization. J Immunol 162(3):1367–1375

    CAS  PubMed  Google Scholar 

  150. Kuhne MR, Lin J, Yablonski D, Mollenauer MN, Ehrlich LI, Huppa J, Davis MM, Weiss A (2003) Linker for activation of T cells, zeta-associated protein-70, and Src homology 2 domain-containing leukocyte protein-76 are required for TCR-induced microtubule-organizing center polarization. J Immunol 171(2):860–866

    CAS  PubMed  Google Scholar 

  151. Lowin-Kropf B, Shapiro VS, Weiss A (1998) Cytoskeletal polarization of T cells is regulated by an immunoreceptor tyrosine-based activation motif-dependent mechanism. J Cell Biol 140(4):861–871

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Quann EJ, Liu X, Altan-Bonnet G, Huse M (2011) A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells. Nat Immunol 12(7):647–654. doi:10.1038/ni.2033

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Quann EJ, Merino E, Furuta T, Huse M (2009) Localized diacylglycerol drives the polarization of the microtubule-organizing center in T cells. Nat Immunol 10(6):627–635

    CAS  PubMed  Google Scholar 

  154. Bertrand F, Esquerre M, Petit AE, Rodrigues M, Duchez S, Delon J, Valitutti S (2010) Activation of the ancestral polarity regulator protein kinase C zeta at the immunological synapse drives polarization of Th cell secretory machinery toward APCs. J Immunol 185(5):2887–2894. doi:10.4049/jimmunol.1000739

    CAS  PubMed  Google Scholar 

  155. Bertrand F, Muller S, Roh KH, Laurent C, Dupre L, Valitutti S (2013) An initial and rapid step of lytic granule secretion precedes microtubule organizing center polarization at the cytotoxic T lymphocyte/target cell synapse. Proc Natl Acad Sci USA 110(15):6073–6078. doi:10.1073/pnas.1218640110

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Etienne-Manneville S (2008) Polarity proteins in migration and invasion. Oncogene 27(55):6970–6980. doi:10.1038/onc.2008.347

    CAS  PubMed  Google Scholar 

  157. Etienne-Manneville S, Hall A (2003) Cell polarity: Par6, aPKC and cytoskeletal crosstalk. Curr Opin Cell Biol 15(1):67–72

    CAS  PubMed  Google Scholar 

  158. Li R, Gundersen GG (2008) Beyond polymer polarity: how the cytoskeleton builds a polarized cell. Nat Rev Mol Cell Biol 9(11):860–873

    CAS  PubMed  Google Scholar 

  159. Ludford-Menting MJ, Oliaro J, Sacirbegovic F, Cheah ET, Pedersen N, Thomas SJ, Pasam A, Iazzolino R, Dow LE, Waterhouse NJ, Murphy A, Ellis S, Smyth MJ, Kershaw MH, Darcy PK, Humbert PO, Russell SM (2005) A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity 22(6):737–748

    CAS  PubMed  Google Scholar 

  160. Combs J, Kim SJ, Tan S, Ligon LA, Holzbaur EL, Kuhn J, Poenie M (2006) Recruitment of dynein to the Jurkat immunological synapse. Proc Natl Acad Sci USA 103(40):14883–14888

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Martin-Cofreces NB, Robles-Valero J, Cabrero JR, Mittelbrunn M, Gordon-Alonso M, Sung CH, Alarcon B, Vazquez J, Sanchez-Madrid F (2008) MTOC translocation modulates IS formation and controls sustained T cell signaling. J Cell Biol 182(5):951–962

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Yi J, Wu X, Chung AH, Chen JK, Kapoor TM, Hammer JA (2013) Centrosome repositioning in T cells is biphasic and driven by microtubule end-on capture-shrinkage. J Cell Biol 202(5):779–792. doi:10.1083/jcb.201301004

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Andres-Delgado L, Anton OM, Bartolini F, Ruiz-Saenz A, Correas I, Gundersen GG, Alonso MA (2012) INF2 promotes the formation of detyrosinated microtubules necessary for centrosome reorientation in T cells. J Cell Biol 198(6):1025–1037. doi:10.1083/jcb.201202137

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Eng CH, Huckaba TM, Gundersen GG (2006) The formin mDia regulates GSK3beta through novel PKCs to promote microtubule stabilization but not MTOC reorientation in migrating fibroblasts. Mol Biol Cell 17(12):5004–5016. doi:10.1091/mbc.E05-10-0914

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Wen Y, Eng CH, Schmoranzer J, Cabrera-Poch N, Morris EJ, Chen M, Wallar BJ, Alberts AS, Gundersen GG (2004) EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. Nat Cell Biol 6(9):820–830

    CAS  PubMed  Google Scholar 

  166. Andres-Delgado L, Anton OM, Alonso MA (2013) Centrosome polarization in T cells: a task for formins. Front Immunol 4:191. doi:10.3389/fimmu.2013.00191

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Chesarone MA, DuPage AG, Goode BL (2010) Unleashing formins to remodel the actin and microtubule cytoskeletons. Nat Rev Mol Cell Biol 11(1):62–74. doi:10.1038/nrm2816

    CAS  PubMed  Google Scholar 

  168. Beal AM, Anikeeva N, Varma R, Cameron TO, Norris PJ, Dustin ML, Sykulev Y (2008) Protein kinase C theta regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL. J Immunol 181(7):4815–4824

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Sasahara Y, Rachid R, Byrne MJ, de la Fuente MA, Abraham RT, Ramesh N, Geha RS (2002) Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Mol Cell 10(6):1269–1281

    CAS  PubMed  Google Scholar 

  170. Dong X, Patino-Lopez G, Candotti F, Shaw S (2007) Structure-function analysis of the WIP role in T cell receptor-stimulated NFAT activation: evidence that WIP-WASP dissociation is not required and that the WIP NH2 terminus is inhibitory. J Biol Chem 282(41):30303–30310. doi:10.1074/jbc.M704972200

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Campi G, Varma R, Dustin ML (2005) Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J Exp Med 202(8):1031–1036

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Yokosuka T, Sakata-Sogawa K, Kobayashi W, Hiroshima M, Hashimoto-Tane A, Tokunaga M, Dustin ML, Saito T (2005) Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat Immunol 6(12):1253–1262

    CAS  PubMed  Google Scholar 

  173. Hashimoto-Tane A, Yokosuka T, Sakata-Sogawa K, Sakuma M, Ishihara C, Tokunaga M, Saito T (2011) Dynein-driven transport of T cell receptor microclusters regulates immune synapse formation and T cell activation. Immunity 34(6):919–931. doi:10.1016/j.immuni.2011.05.012

    CAS  PubMed  Google Scholar 

  174. Vardhana S, Choudhuri K, Varma R, Dustin ML (2010) Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster. Immunity 32(4):531–540. doi:10.1016/j.immuni.2010.04.005

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Mossman KD, Campi G, Groves JT, Dustin ML (2005) Altered TCR signaling from geometrically repatterned immunological synapses. Science 310(5751):1191–1193

    CAS  PubMed  Google Scholar 

  176. Anitei M, Hoflack B (2012) Bridging membrane and cytoskeleton dynamics in the secretory and endocytic pathways. Nat Cell Biol 14(1):11–19

    CAS  Google Scholar 

  177. Chaturvedi A, Martz R, Dorward D, Waisberg M, Pierce SK (2011) Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments. Nat Immunol 12(11):1119–1126. doi:10.1038/ni.2116

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285(5425):221–227

    CAS  PubMed  Google Scholar 

  179. Hyun YM, Lefort CT, Kim M (2009) Leukocyte integrins and their ligand interactions. Immunol Res. doi:10.1007/s12026-009-8101-1

    PubMed Central  PubMed  Google Scholar 

  180. Kinashi T (2005) Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev 5(7):546–559. doi:10.1038/nri1646

    CAS  Google Scholar 

  181. Nolz JC, Nacusi LP, Segovis CM, Medeiros RB, Mitchell JS, Shimizu Y, Billadeau DD (2008) The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1. J Cell Biol 182(6):1231–1244

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Wernimont SA, Wiemer AJ, Bennin DA, Monkley SJ, Ludwig T, Critchley DR, Huttenlocher A (2011) Contact-dependent T cell activation and T cell stopping require talin1. J Immunol 187(12):6256–6267. doi:10.4049/jimmunol.1102028

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Nguyen K, Sylvain NR, Bunnell SC (2008) T cell costimulation via the integrin VLA-4 inhibits the actin-dependent centralization of signaling microclusters containing the adaptor SLP-76. Immunity 28(6):810–821. doi:10.1016/j.immuni.2008.04.019

    CAS  PubMed  Google Scholar 

  184. Beal AM, Anikeeva N, Varma R, Cameron TO, Vasiliver-Shamis G, Norris PJ, Dustin ML, Sykulev Y (2009) Kinetics of early T cell receptor signaling regulate the pathway of lytic granule delivery to the secretory domain. Immunity 31(4):632–642. doi:10.1016/j.immuni.2009.09.004

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Natkanski E, Lee WY, Mistry B, Casal A, Molloy JE, Tolar P (2013) B cells use mechanical energy to discriminate antigen affinities. Science 340(6140):1587–1590. doi:10.1126/science.1237572

    CAS  PubMed Central  PubMed  Google Scholar 

  186. Zhang F, Wen Y, Guo X (2014) CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum Mol Genet. doi:10.1093/hmg/ddu125

    Google Scholar 

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Authors and Affiliations

  1. Immunology Program, Memorial Sloan-Kettering Cancer Center, Box 514, 1275 York Ave, New York, NY, 10065, USA

    Audrey Le Floc’h & Morgan Huse

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  1. Audrey Le Floc’h
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  2. Morgan Huse
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Correspondence to Morgan Huse.

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Le Floc’h, A., Huse, M. Molecular mechanisms and functional implications of polarized actin remodeling at the T cell immunological synapse. Cell. Mol. Life Sci. 72, 537–556 (2015). https://doi.org/10.1007/s00018-014-1760-7

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  • DOI: https://doi.org/10.1007/s00018-014-1760-7

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