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Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

  • Robbert Hoogeboom
  • Pavel TolarEmail author
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 393)

Abstract

Generation of high-affinity, protective antibodies requires B cell receptor (BCR) signaling, as well as antigen internalization and presentation to helper T cells. B cell antigen internalization is initiated by antigen capture, either from solution or from immune synapses formed on the surface of antigen-presenting cells, and proceeds via clathrin-dependent endocytosis and intracellular routing to late endosomes. Although the components of this pathway are still being discovered, it has become clear that antigen internalization is actively regulated by BCR signaling at multiple steps and, vice versa, that localization of the BCR along the endocytic pathway modulates signaling. Accordingly, defects in BCR internalization or trafficking contribute to enhanced B cell activation in models of autoimmune diseases and in B cell lymphomas. In this review, we discuss how BCR signaling complexes regulate each of the steps of this endocytic process and why defects along this pathway manifest as hyperactive B cell responses in vivo.

Keywords

Actin Polymerization Early Endosome Late Endosome Phosphatidyl Inositol Immune Synapse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors’ research has been supported by the UK Medical Research Council (Unit Programme number U117597138) and by the Francis Crick Institute. PT is supported by the EMBO Young Investigator Programme. RH is supported by a Rubicon grant from the Netherlands Organisation for Scientific Research (NWO).

References

  1. Aluvihare VR, Khamlichi AA, Williams GT et al (1997) Acceleration of intracellular targeting of antigen by the B-cell antigen receptor: importance depends on the nature of the antigen-antibody interaction. EMBO J 16:3553–3562PubMedPubMedCentralGoogle Scholar
  2. Anitei M, Hoflack B (2012) Bridging membrane and cytoskeleton dynamics in the secretory and endocytic pathways. Nat Cell Biol 14:11–19Google Scholar
  3. Arana E, Vehlow A, Harwood NE et al (2008) Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 28:88–99PubMedGoogle Scholar
  4. Batista FD, Iber D, Neuberger MS (2001) B cells acquire antigen from target cells after synapse formation. Nature 411:489–494PubMedGoogle Scholar
  5. Becker-Herman S, Meyer-Bahlburg A, Schwartz MA et al (2011) WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J Exp Med 208:2033–2042PubMedPubMedCentralGoogle Scholar
  6. Bonazzi M, Vasudevan L, Mallet A et al (2011) Clathrin phosphorylation is required for actin recruitment at sites of bacterial adhesion and internalization. J Cell Biol 195:525–536PubMedPubMedCentralGoogle Scholar
  7. Boulant S, Kural C, Zeeh J-C et al (2011) Actin dynamics counteract membrane tension during clathrin-mediated endocytosis. Nat Cell Biol 13:1124–1131PubMedPubMedCentralGoogle Scholar
  8. Burbage M, Keppler SJ, Gasparrini F et al (2014) Cdc42 is a key regulator of B cell differentiation and is required for antiviral humoral immunity. J Exp Med 369:113Google Scholar
  9. Busman-Sahay K, Drake L, Sitaram A et al (2013) Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs. PLoS ONE 8:e54938PubMedPubMedCentralGoogle Scholar
  10. Caballero A, Katkere B, Wen X-Y et al (2006) Functional and structural requirements for the internalization of distinct BCR-ligand complexes. Eur J Immunol 36:3131–3145PubMedPubMedCentralGoogle Scholar
  11. Carrasco YR, Batista FD (2006a) B cell recognition of membrane-bound antigen: an exquisite way of sensing ligands. Curr Opin Immunol 18:286–291PubMedPubMedCentralGoogle Scholar
  12. Carrasco YR, Batista FDA (2006b) B-cell activation by membrane-bound antigens is facilitated by the interaction of VLA-4 with VCAM-1. EMBO J 25:889–899PubMedPubMedCentralGoogle Scholar
  13. Carrasco YR, Batista FD (2007) B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27:160–171PubMedPubMedCentralGoogle Scholar
  14. Carrasco YR, Fleire SJ, Cameron T et al (2004) LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation. Immunity 20:589–599PubMedPubMedCentralGoogle Scholar
  15. Chatterjee P, Tiwari RK, Rath S et al (2012) Modulation of antigen presentation and B cell receptor signaling in B cells of beige mice. J Immunol 188:2695–2702PubMedPubMedCentralGoogle Scholar
  16. Chaturvedi A, Dorward D, Pierce SK (2008) The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyper-responses to DNA-containing antigens. Immunity 28:799–809PubMedPubMedCentralGoogle Scholar
  17. Chaturvedi A, Martz R, Dorward D et al (2011) Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments. Nat Immunol 12:1119–1126PubMedPubMedCentralGoogle Scholar
  18. Cinamon G, Zachariah MA, Lam OM et al (2008) Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol 9:54–62PubMedPubMedCentralGoogle Scholar
  19. Clark MR, Johnson SA, Cambier JC (1994) Analysis of Ig-α-tyrosine kinase interaction reveals two levels of binding specificity and tyrosine phosphorylated Ig-α stimulation of Fyn activity. EMBO J 13:1911–1919Google Scholar
  20. Cocucci E, Aguet F, Boulant S, Kirchhausen T (2012) The first five seconds in the life of a Clathrin-coated pit. Cell 150:495–507PubMedPubMedCentralGoogle Scholar
  21. Cyster JG (2010) B cell follicles and antigen encounters of the third kind. Nat Immunol 11:989PubMedPubMedCentralGoogle Scholar
  22. Davis RE, Ngo VN, Lenz G et al (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463:88–92PubMedPubMedCentralGoogle Scholar
  23. Depoil D, Fleire S, Treanor BL et al (2008) CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nat Immunol 9:63–72PubMedGoogle Scholar
  24. Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902PubMedPubMedCentralGoogle Scholar
  25. Dykstra ML, Longnecker R, Pierce SK (2001) Epstein-barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR. Immunity 14:57–67PubMedPubMedCentralGoogle Scholar
  26. Ehrlich M, Boll W, Van Oijen A et al (2004) Endocytosis by random initiation and stabilization of clathrin-coated pits. Cell 118:591–605PubMedPubMedCentralGoogle Scholar
  27. Engqvist-Goldstein ÅEY, Kessels MM, Chopra VS et al (1999) An actin-binding protein of the Sla2/Huntingtin interacting protein 1 family is a novel component of clathrin-coated pits and vesicles. J Cell Biol 147:1503–1518PubMedPubMedCentralGoogle Scholar
  28. Ferguson AR, Youd ME, Corley RB (2004) Marginal zone B cells transport and deposit IgM-containing immune complexes onto follicular dendritic cells. Int Immunol 16:1411–1422PubMedPubMedCentralGoogle Scholar
  29. Ferguson SM, Raimondi A, Paradise S et al (2009) Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits. Dev Cell 17:811–822PubMedPubMedCentralGoogle Scholar
  30. Fleire SJ, Goldman JP, Carrasco YR et al (2006) B cell ligand discrimination through a spreading and contraction response. Science 312:738–741PubMedCentralGoogle Scholar
  31. Freeman SA, Lei V, Dang-Lawson M et al (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 187:5887–5900PubMedPubMedCentralGoogle Scholar
  32. Gao J, Ma X, Gu W et al (2012) Novel functions of murine B1 cells: active phagocytic and microbicidal abilities. Eur J Immunol 42:982–992PubMedPubMedCentralGoogle Scholar
  33. Gazumyan A, Reichlin A, Nussenzweig MC (2006) Ig β tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization. J Exp Med 203:1785–1794PubMedPubMedCentralGoogle Scholar
  34. Gonzalez SF, Lukacs-Kornek V, Kuligowski MP et al (2010) Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes. Nat Immunol 11:427–434PubMedPubMedCentralGoogle Scholar
  35. Granger E, McNee G, Allan V, Woodman P (2014) The role of the cytoskeleton and molecular motors in endosomal dynamics. Semin Cell Dev Biol 31:20–29PubMedPubMedCentralGoogle Scholar
  36. Haugh JM, Schooler K, Wells A et al (1999) Effect of epidermal growth factor receptor internalization on regulation of the phospholipase C-γ1 signaling pathway. J Biol Chem 274:8958–8965PubMedGoogle Scholar
  37. Heesters BA, Chatterjee P, Kim Y-A et al (2013) Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell antigen binding and activation. Immunity 38:1164–1175PubMedPubMedCentralGoogle Scholar
  38. Hou P, Araujo E, Zhao T et al (2006) B cell antigen receptor signaling and internalization are mutually exclusive events. PLoS Biol 4:e200PubMedPubMedCentralGoogle Scholar
  39. Itoh K, Shimono K, Lemmon V (2005) Dephosphorylation and internalization of cell adhesion molecule L1 induced by theta burst stimulation in rat hippocampus. Mol Cell Neurosci 29:245–249PubMedPubMedCentralGoogle Scholar
  40. Jackson LP, Kelly BT, McCoy AJ et al (2010) A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex. Cell 141:1220–1229PubMedPubMedCentralGoogle Scholar
  41. Jang C, Machtaler S, Matsuuchi L (2010) The role of Ig-α/β in B cell antigen receptor internalization. Immunol Lett 134:75–82PubMedPubMedCentralGoogle Scholar
  42. Jean S, Cox S, Schmidt EJ et al (2012) Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling. Mol Biol Cell 23:2723–2740PubMedPubMedCentralGoogle Scholar
  43. Junt T, Moseman EA, Iannacone M et al (2007) Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450:110–114PubMedPubMedCentralGoogle Scholar
  44. Katkere B, Rosa S, Drake JR (2012) The Syk-binding ubiquitin ligase c-Cbl mediates signaling-dependent B cell receptor ubiquitination and B cell receptor-mediated antigen processing and presentation. J Biol Chem 287:16636–16644PubMedPubMedCentralGoogle Scholar
  45. Kiss RS, Nilsson T (2014) Rab proteins implicated in lipid storage and mobilization. J Biomed Res 28:169–177PubMedPubMedCentralGoogle Scholar
  46. Kitaura Y, Jang IK, Wang Y et al (2007) Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. Immunity 26:567–578PubMedPubMedCentralGoogle Scholar
  47. Li J, Barreda DR, Zhang Y-A et al (2006) B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities. Nat Immunol 7:1116–1124PubMedPubMedCentralGoogle Scholar
  48. Lin KBL, Freeman SA, Zabetian S et al (2008) The rap GTPases regulate B cell morphology, immune-synapse formation, and signaling by particulate B cell receptor ligands. Immunity 28:75–87PubMedPubMedCentralGoogle Scholar
  49. Liu AP, Aguet F, Danuser G, Schmid SL (2010) Local clustering of transferrin receptors promotes clathrin-coated pit initiation. J Cell Biol 191:1381–1393PubMedPubMedCentralGoogle Scholar
  50. Liu C, Bai X, Wu J et al (2013) N-WASP is essential for the negative regulation of B cell receptor signaling. PLoS Biol 11:e1001704PubMedPubMedCentralGoogle Scholar
  51. Ma H, Yankee TM, Hu J et al (2001) Visualization of Syk-antigen receptor interactions using green fluorescent protein: differential roles for Syk and Lyn in the regulation of receptor capping and internalization. J Immunol 166:1507–1516PubMedGoogle Scholar
  52. Malhotra S, Kovats S, Zhang W, Coggeshall KM (2009) Vav and Rac activation in B cell antigen receptor endocytosis involves Vav recruitment to the adapter protein LAB. J Biol Chem 284:36202–36212PubMedPubMedCentralGoogle Scholar
  53. Martin F, Oliver AM, Kearney JF (2001) Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14:617–629PubMedGoogle Scholar
  54. Matsumoto M, Oyamada K, Takahashi H et al (2009) Large-scale proteomic analysis of tyrosine-phosphorylation induced by T-cell receptor or B-cell receptor activation reveals new signaling pathways. Proteomics 9:3549–3563PubMedGoogle Scholar
  55. Maxfield FR, McGraw TE (2004) Endocytic recycling. Nat Rev Mol Cell Biol 5:121–132PubMedGoogle Scholar
  56. McLeod SJ, Ingham RJ, Bos JL et al (1998) Activation of the Rap1 GTPase by the B cell antigen receptor. J Biol Chem 273:29218–29223PubMedGoogle Scholar
  57. Miaczynska M, Christoforidis S, Giner A et al (2004) APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 116:445–456PubMedPubMedCentralGoogle Scholar
  58. Minden MD-V, Übelhart R, Schneider D et al (2013) Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 489:309–312Google Scholar
  59. Monks C, Freiberg B, Kupfer H et al (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82–86PubMedPubMedCentralGoogle Scholar
  60. Natkanski E, Lee W-Y, Mistry B et al (2013) B cells use mechanical energy to discriminate antigen affinities. Science 340:1587–1590PubMedPubMedCentralGoogle Scholar
  61. Ngo VN, Young RM, Schmitz R et al (2012) Oncogenically active MYD88 mutations in human lymphoma. Nature 469:115–119Google Scholar
  62. Niiro H, Allam A, Stoddart A et al (2004) The B lymphocyte adaptor molecule of 32 kilodaltons (Bam32) regulates B cell antigen receptor internalization. J Immunol 173:5601–5609PubMedGoogle Scholar
  63. Onabajo OO, Seeley MK, Kale A et al (2008) Actin-binding protein 1 regulates B cell receptor-mediated antigen processing and presentation in response to B cell receptor activation. J Immunol 180:6685–6695PubMedPubMedCentralGoogle Scholar
  64. O’Neill S, Veselits M, Zhang M et al (2009) Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells. PNAS 106:6262–6267PubMedGoogle Scholar
  65. O’Neill SK, Getahun A, Gauld SB et al (2011) Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 35:746–756PubMedPubMedCentralGoogle Scholar
  66. Pape KA, Catron DM, Itano AA, Jenkins MK (2007) The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity 26:491–502PubMedGoogle Scholar
  67. Parameswaran N, Enyindah-Asonye G, Bagheri N et al (2013) Spatial coupling of JNK activation to the B cell antigen receptor by tyrosine-phosphorylated ezrin. J Immunol 190:2017–2026PubMedPubMedCentralGoogle Scholar
  68. Phan TG, Grigorova I, Okada T, Cyster JG (2007) Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat Immunol 8:992–1000PubMedGoogle Scholar
  69. Piper RC, Lehner PJ (2011) Endosomal transport via ubiquitination. Trends Cell Biol 21:647–655PubMedPubMedCentralGoogle Scholar
  70. Pore D, Pore D, Parameswaran N et al (2013) Ezrin tunes the magnitude of humoral immunity. J Immunol 191:4048–4058PubMedGoogle Scholar
  71. Posor Y, Eichhorn-Gruenig M, Puchkov D et al (2013) Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Nature 499:233–237PubMedGoogle Scholar
  72. Puga I, Cols M, Barra CM et al (2012) B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13:170–180Google Scholar
  73. Qi H, Egen JG, Huang AYC, Germain RN (2006) Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312:1672–1676PubMedPubMedCentralGoogle Scholar
  74. Randall KL, Lambe T, Johnson A et al (2009) Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat Immunol 10:1283–1291PubMedPubMedCentralGoogle Scholar
  75. Roozendaal R, Mempel TR, Pitcher LA et al (2009) Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity 30:264–276PubMedPubMedCentralGoogle Scholar
  76. Saez de Guinoa J, Barrio L, Carrasco YR (2013) Vinculin arrests motile B cells by stabilizing integrin clustering at the immune synapse. J Immunol 191:2742–2751PubMedGoogle Scholar
  77. Sáez de Guinoa J, Barrio L, Mellado M, Carrasco YR (2011) CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics. Blood 118:1560–1569PubMedGoogle Scholar
  78. Satpathy S, Wagner SA, Beli P, et al (2015) Systems-wide analysis of the BCR signaling complexes and the downstream phosphorylation and ubiquitylation. Mol Syst Biol 11:810Google Scholar
  79. Schnyder T, Castello A, Feest C et al (2011) B cell receptor-mediated antigen gathering requires ubiquitin ligase Cbl and adaptors Grb2 and Dok-3to recruit dynein to the signaling microcluster. Immunity 34:905–918PubMedPubMedCentralGoogle Scholar
  80. Schwickert TA, Victora GD, Fooksman DR et al (2011) A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J Exp Med 208:1243–1252PubMedPubMedCentralGoogle Scholar
  81. Seeley-Fallen MK, Liu LJ, Shapiro MR et al (2014) Actin-binding protein 1 links B-cell antigen receptors to negative signaling pathways. PNAS 111:9881–9886PubMedPubMedCentralGoogle Scholar
  82. Sharma S, Orlowski G, Song W (2009) Btk regulates B cell receptor-mediated antigen processing and presentation by controlling actin cytoskeleton dynamics in B cells. J Immunol 182:329–339PubMedPubMedCentralGoogle Scholar
  83. Shih T-AY, Meffre E, Roederer M, Nussenzweig MC (2002) Role of BCR affinity in T cell dependent antibody responses in vivo. Nat Immunol 3:570–575PubMedPubMedCentralGoogle Scholar
  84. Shin H-W, Hayashi M, Christoforidis S et al (2005) An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J Cell Biol 170:607–618PubMedPubMedCentralGoogle Scholar
  85. Sohn HW, Gu H, Pierce SK (2003) Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. J Exp Med 197:1511–1524PubMedPubMedCentralGoogle Scholar
  86. Song W, Liu C, Seeley-Fallen MK et al (2013) Actin-mediated feedback loops in B-cell receptor signaling. Immunol Rev 256:177–189PubMedPubMedCentralGoogle Scholar
  87. Souwer Y, Griekspoor A, Jorritsma T et al (2009) B cell receptor-mediated internalization of salmonella: a novel pathway for autonomous B cell activation and antibody production. J Immunol 182:7473–7481PubMedPubMedCentralGoogle Scholar
  88. Stoddart A, Dykstra ML, Brown BK et al (2002) Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization. Immunity 17:451–462PubMedPubMedCentralGoogle Scholar
  89. Stoddart A, Jackson AP, Brodsky F (2005) Plasticity of B cell receptor internalization upon conditional depletion of clathrin. Mol Biol Cell 16:2339–2348PubMedPubMedCentralGoogle Scholar
  90. Suzuki K, Grigorova I, Phan TG et al (2009) Visualizing B cell capture of cognate antigen from follicular dendritic cells. J Exp Med 206:1485–1493PubMedPubMedCentralGoogle Scholar
  91. Tanno H, Yamaguchi T, Goto E et al (2012) The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane. Mol Biol Cell 23:1343–1353PubMedPubMedCentralGoogle Scholar
  92. Tolar P, Spillane KM (2014) Force generation in B-cell synapses: mechanisms coupling B-cell receptor binding to antigen internalization and affinity discrimination. Adv Immunol 123:69–100Google Scholar
  93. Tolar P, Hanna J, Krueger PD, Pierce SK (2009) The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens. Immunity 30:44–55PubMedPubMedCentralGoogle Scholar
  94. Treanor B, Depoil D, Bruckbauer A, Batista FD (2011) Dynamic cortical actin remodeling by ERM proteins controls BCR microcluster organization and integrity. J Exp Med 208:1055–1068PubMedPubMedCentralGoogle Scholar
  95. Veselits M, Tanaka A, Lipkowitz S et al (2014) Recruitment of Cbl-b to B cell antigen receptor couples antigen recognition to toll-like receptor 9 activation in late endosomes. PLoS ONE 9:e89792PubMedPubMedCentralGoogle Scholar
  96. Victora GD, Schwickert TA, Fooksman DR et al (2010) Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143:592–605PubMedPubMedCentralGoogle Scholar
  97. Weber M, Treanor B, Depoil D et al (2008) Phospholipase C-γ2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen. J Exp Med 205:853–868PubMedPubMedCentralGoogle Scholar
  98. Yuseff M-I, Reversat A, Lankar D et al (2011) Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation. Immunity 35:361–374PubMedPubMedCentralGoogle Scholar
  99. Zhang M, Veselits M, O’Neill S et al (2007) Ubiquitinylation of Igβ dictates the endocytic fate of the B cell antigen receptor. J Immunol 179:4435–4443PubMedPubMedCentralGoogle Scholar
  100. Zoncu R, Perera RM, Balkin DM et al (2009) A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 136:1110–1121PubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Immune Cell BiologyNational Institute for Medical Research, Francis Crick Institute, Mill Hill LaboratoryLondonUK

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