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T Cell Microvilli: Finger-Shaped External Structures Linked to the Fate of T Cells

  • Hye-Ran Kim (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Jeong-Su Park (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Won-Chang Soh (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Na-Young Kim (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Hyun-Yoong Moon (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Ji-Su Lee (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Chang-Duk Jun (School of Life Sciences, Gwangju Institute of Science and Technology (GIST))
  • Received : 2022.12.25
  • Accepted : 2023.02.11
  • Published : 2023.02.28
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Abstract

Microvilli are outer membrane organelles that contain cross-linked filamentous actin. Unlike well-characterized epithelial microvilli, T-cell microvilli are dynamic similar to those of filopodia, which grow and shrink intermittently via the alternate actin-assembly and -disassembly. T-cell microvilli are specialized for sensing Ags on the surface of Ag-presenting cells (APCs). Thus, these finger-shaped microprotrusions contain many signaling-related proteins and can serve as a signaling platforms that induce intracellular signals. However, they are not limited to sensing external information but can provide sites for parts of the cell-body to tear away from the cell. Cells are known to produce many types of extracellular vesicles (EVs), such as exosomes, microvesicles, and membrane particles. T cells also produce EVs, but little is known about under what conditions T cells generate EVs and which types of EVs are released. We discovered that T cells produce few exosomes but release large amounsts of microvilli-derived particles during physical interaction with APCs. Although much is unanswered as to why T cells use the same organelles to sense Ags or to produce EVs, these events can significantly affect T cell fate, including clonal expansion and death. Since TCRs are localized at microvilli tips, this membrane event also raises a new question regarding long-standing paradigm in T cell biology; i.e., surface TCR downmodulation following T cell activation. Since T-cell microvilli particles carry T-cell message to their cognate partner, these particles are termed T-cell immunological synaptosomes (TISs). We discuss the potential physiological role of TISs and their application to immunotherapies.

Keywords

Acknowledgement

This work was supported by the Creative Research Initiative Program (2015R1A3A2066253) through National Research Foundation (NRF) grants funded by the Ministry of Science and ICT (MSIT), the Basic Science Program (2022R1A2C4002627) through National Research Foundation (NRF) grants funded by the Ministry of Education (MOE), and supported by Global University Project (GUP), GIST Research Institute (GRI) IBBR grant funded by the GIST (in 2021-2022), and the Joint Research Project of Institutes of Science and Technology (2021-2022), Korea.

References

  1. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. The immunological synapse: a molecular machine controlling T cell activation. Science 1999;285:221-227. 
  2. Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 1998;395:82-86. 
  3. Stinchcombe JC, Bossi G, Booth S, Griffiths GM. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 2001;15:751-761. 
  4. Carlin LM, Eleme K, McCann FE, Davis DM. Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses. J Exp Med 2001;194:1507-1517. 
  5. Dustin ML, Cooper JA. The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling. Nat Immunol 2000;1:23-29. 
  6. Griffiths GM, Tsun A, Stinchcombe JC. The immunological synapse: a focal point for endocytosis and exocytosis. J Cell Biol 2010;189:399-406. 
  7. Dustin ML. T-cell activation through immunological synapses and kinapses. Immunol Rev 2008;221:77-89. 
  8. Piragyte I, Jun CD. Actin engine in immunological synapse. Immune Netw 2012;12:71-83. 
  9. Choudhuri K, Llodra J, Roth EW, Tsai J, Gordo S, Wucherpfennig KW, Kam LC, Stokes DL, Dustin ML. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 2014;507:118-123. 
  10. Schamel WW, Alarcon B. Organization of the resting TCR in nanoscale oligomers. Immunol Rev 2013;251:13-20. 
  11. Schamel WW, Arechaga I, Risueno RM, van Santen HM, Cabezas P, Risco C, Valpuesta JM, Alarcon B. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J Exp Med 2005;202:493-503. 
  12. Molnar E, Swamy M, Holzer M, Beck-Garcia K, Worch R, Thiele C, Guigas G, Boye K, Luescher IF, Schwille P, et al. Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. J Biol Chem 2012;287:42664-42674.
  13. Beck-Garcia K, Beck-Garcia E, Bohler S, Zorzin C, Sezgin E, Levental I, Alarcon B, Schamel WW. Nanoclusters of the resting T cell antigen receptor (TCR) localize to non-raft domains. Biochim Biophys Acta 2015;1853:802-809. 
  14. Crites TJ, Padhan K, Muller J, Krogsgaard M, Gudla PR, Lockett SJ, Varma R. TCR Microclusters pre-exist and contain molecules necessary for TCR signal transduction. J Immunol 2014;193:56-67. 
  15. Lillemeier BF, Mortelmaier MA, Forstner MB, Huppa JB, Groves JT, Davis MM. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat Immunol 2010;11:90-96. 
  16. Siegers GM, Swamy M, Fernandez-Malave E, Minguet S, Rathmann S, Guardo AC, Perez-Flores V, Regueiro JR, Alarcon B, Fisch P, et al. Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies. J Exp Med 2007;204:2537-2544. 
  17. Wilson BS, Pfeiffer JR, Surviladze Z, Gaudet EA, Oliver JM. High resolution mapping of mast cell membranes reveals primary and secondary domains of Fc(ε)RI and LAT. J Cell Biol 2001;154:645-658. 
  18. Jung Y, Riven I, Feigelson SW, Kartvelishvily E, Tohya K, Miyasaka M, Alon R, Haran G. Threedimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies. Proc Natl Acad Sci U S A 2016;113:E5916-E5924. 
  19. Cai E, Marchuk K, Beemiller P, Beppler C, Rubashkin MG, Weaver VM, Gerard A, Liu TL, Chen BC, Betzig E, et al. Visualizing dynamic microvillar search and stabilization during ligand detection by T cells. Science 2017;356:eaal3118. 
  20. Kim HR, Mun Y, Lee KS, Park YJ, Park JS, Park JH, Jeon BN, Kim CH, Jun Y, Hyun YM, et al. T cell microvilli constitute immunological synaptosomes that carry messages to antigen-presenting cells. Nat Commun 2018;9:3630-3648. 
  21. Yi JC, Samelson LE. Microvilli set the stage for T-cell activation. Proc Natl Acad Sci U S A 2016;113:11061-11062. 
  22. He HT, Lellouch A, Marguet D. Lipid rafts and the initiation of T cell receptor signaling. Semin Immunol 2005;17:23-33. 
  23. Harder T. Lipid raft domains and protein networks in T-cell receptor signal transduction. Curr Opin Immunol 2004;16:353-359. 
  24. Cebecauer M. Role of lipids in morphogenesis of T-cell microvilli. Front Immunol 2021;12:613591. 
  25. Ikenouchi J, Hirata M, Yonemura S, Umeda M. Sphingomyelin clustering is essential for the formation of microvilli. J Cell Sci 2013;126:3585-3592. 
  26. Ghosh S, Di Bartolo V, Tubul L, Shimoni E, Kartvelishvily E, Dadosh T, Feigelson SW, Alon R, Alcover A, Haran G. ERM-dependent assembly of T cell receptor signaling and co-stimulatory molecules on microvilli prior to activation. Cell Reports 2020;30:3434-3447.e6. 
  27. Kim HR, Jun CD. T cell microvilli: sensors or senders? Front Immunol 2019;10:1753. 
  28. Danielsen EM, Hansen GH. Lipid rafts in epithelial brush borders: atypical membrane microdomains with specialized functions. Biochim Biophys Acta 2003;1617:1-9. 
  29. Majstoravich S, Zhang J, Nicholson-Dykstra S, Linder S, Friedrich W, Siminovitch KA, Higgs HN. Lymphocyte microvilli are dynamic, actin-dependent structures that do not require Wiskott-Aldrich syndrome protein (WASp) for their morphology. Blood 2004;104:1396-1403. 
  30. Gupton SL, Gertler FB. Filopodia: the fingers that do the walking. Sci STKE 2007;2007:re5. 
  31. Yang C, Svitkina T. Filopodia initiation: focus on the Arp2/3 complex and formins. Cell Adhes Migr 2011;5:402-408.
  32. Le Clainche C, Carlier MF. Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol Rev 2008;88:489-513. 
  33. Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL, Butcher EC. α4 Integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 1995;80:413-422. 
  34. von Andrian UH, Hasslen SR, Nelson RD, Erlandsen SL, Butcher EC. A central role for microvillous receptor presentation in leukocyte adhesion under flow. Cell 1995;82:989-999. 
  35. Lange K. Fundamental role of microvilli in the main functions of differentiated cells: outline of an universal regulating and signaling system at the cell periphery. J Cell Physiol 2011;226:896-927. 
  36. Long H, Zhang F, Xu N, Liu G, Diener DR, Rosenbaum JL, Huang K. Comparative analysis of ciliary membranes and ectosomes. Curr Biol 2016;26:3327-3335. 
  37. Molday RS, Goldberg AF. Peripherin diverts ciliary ectosome release to photoreceptor disc morphogenesis. J Cell Biol 2017;216:1227-1229. 
  38. Wood CR, Rosenbaum JL. Ciliary ectosomes: transmissions from the cell's antenna. Trends Cell Biol 2015;25:276-285. 
  39. Veziroglu EM, Mias GI. Characterizing extracellular vesicles and their diverse RNA contents. Front Genet 2020;11:700. 
  40. Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015;4:27066. 
  41. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009;9:581-593. 
  42. Osaki M, Okada F. Exosomes and their role in cancer progression. Yonago Acta Med 2019;62:182-190. 
  43. Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci 2019;9:19. 
  44. Rudraprasad D, Rawat A, Joseph J. Exosomes, extracellular vesicles and the eye. Exp Eye Res 2022;214:108892. 
  45. van der Pol E, Boing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 2012;64:676-705. 
  46. Gutierrez-Vazquez C, Villarroya-Beltri C, Mittelbrunn M, Sanchez-Madrid F. Transfer of extracellular vesicles during immune cell-cell interactions. Immunol Rev 2013;251:125-142. 
  47. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013;200:373-383. 
  48. Corrado C, Raimondo S, Chiesi A, Ciccia F, De Leo G, Alessandro R. Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci 2013;14:5338-5366. 
  49. Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 2012;21:R125-R134. 
  50. Meldolesi J. Exosomes and ectosomes in intercellular communication. Curr Biol 2018;28:R435-R444. 
  51. Wilson HL, Francis SE, Dower SK, Crossman DC. Secretion of intracellular IL-1 receptor antagonist (type 1) is dependent on P2X7 receptor activation. J Immunol 2004;173:1202-1208.
  52. Kuo L, Freed EO. ARRDC1 as a mediator of microvesicle budding. Proc Natl Acad Sci U S A 2012;109:4025-4026. 
  53. Puca L, Chastagner P, Meas-Yedid V, Israel A, Brou C. A-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals. J Cell Sci 2013;126:4457-4468. 
  54. Nabhan JF, Hu R, Oh RS, Cohen SN, Lu Q. Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc Natl Acad Sci U S A 2012;109:4146-4151. 
  55. Saliba DG, Cespedes-Donoso PF, Balint S, Compeer EB, Korobchevskaya K, Valvo S, Mayya V, Kvalvaag A, Peng Y, Dong T, et al. Composition and structure of synaptic ectosomes exporting antigen receptor linked to functional CD40 ligand from helper T cells. eLife 2019;8:e47528. 
  56. Finetti F, Cassioli C, Baldari CT. Transcellular communication at the immunological synapse: a vesicular traffic-mediated mutual exchange. F1000 Res 2017;6:1880. 
  57. Zakharova L, Svetlova M, Fomina AF. T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor. J Cell Physiol 2007;212:174-181. 
  58. Cai Z, Yang F, Yu L, Yu Z, Jiang L, Wang Q, Yang Y, Wang L, Cao X, Wang J. Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J Immunol 2012;188:5954-5961. 
  59. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C, Raposo G, Hivroz C. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol 2002;168:3235-3241. 
  60. Dustin ML, Springer TA. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature 1989;341:619-624. 
  61. Hsu CJ, Hsieh WT, Waldman A, Clarke F, Huseby ES, Burkhardt JK, Baumgart T. Ligand mobility modulates immunological synapse formation and T cell activation. PLoS One 2012;7:e32398. 
  62. Pelissier Vatter FA, Cioffi M, Hanna SJ, Castarede I, Caielli S, Pascual V, Matei I, Lyden D. Extracellular vesicle- and particle-mediated communication shapes innate and adaptive immune responses. J Exp Med 2021;218:e20202579. 
  63. Kong H, Kim SB. Exosomal communication between the tumor microenvironment and innate immunity and its therapeutic application. Immune Netw 2022;22:e38. 
  64. Besnard AG, Togbe D, Guillou N, Erard F, Quesniaux V, Ryffel B. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur J Immunol 2011;41:1675-1686. 
  65. Trevejo JM, Marino MW, Philpott N, Josien R, Richards EC, Elkon KB, Falck-Pedersen E. TNF-α-dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection. Proc Natl Acad Sci U S A 2001;98:12162-12167. 
  66. Schall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 1990;347:669-671. 
  67. Smith CM, Wilson NS, Waithman J, Villadangos JA, Carbone FR, Heath WR, Belz GT. Cognate CD4+  T cell licensing of dendritic cells in CD8+  T cell immunity. Nat Immunol 2004;5:1143-1148. 
  68. Zhu DM, Dustin ML, Cairo CW, Thatte HS, Golan DE. Mechanisms of cellular avidity regulation in CD2- CD58-mediated T cell adhesion. ACS Chem Biol 2006;1:649-658. 
  69. Naseri M, Bozorgmehr M, Zoller M, Ranaei Pirmardan E, Madjd Z. Tumor-derived exosomes: the next generation of promising cell-free vaccines in cancer immunotherapy. OncoImmunology 2020;9:1779991. 
  70. Sun S, Hao H, Yang G, Zhang Y, Fu Y. Immunotherapy with CAR-modified T cells: toxicities and overcoming strategies. J Immunol Res 2018;2018:2386187.
  71. Perica K, Varela JC, Oelke M, Schneck J. Adoptive T cell immunotherapy for cancer. Rambam Maimonides Med J 2015;6:e0004. 
  72. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767-811. 
  73. Perez CR, De Palma M. Engineering dendritic cell vaccines to improve cancer immunotherapy. Nat Commun 2019;10:5408-5417. 
  74. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med 2016;14:73. 
  75. Almasbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res 2016;2016:5474602. 
  76. Anurathapan U, Leen AM, Brenner MK, Vera JF. Engineered T cells for cancer treatment. Cytotherapy 2014;16:713-733. 
  77. Riviere I, Sadelain M. Chimeric antigen receptors: a cell and gene therapy perspective. Mol Ther 2017;25:1117-1124. 
  78. Ho NI, Huis In 't Veld LG, Raaijmakers TK, Adema GJ. Adjuvants enhancing cross-presentation by dendritic cells: the key to more effective vaccines? Front Immunol 2018;9:2874. 
  79. McAleer JP, Vella AT. Understanding how lipopolysaccharide impacts CD4 T-cell immunity. Crit Rev Immunol 2008;28:281-299. 
  80. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-252. 
  81. Beacock-Sharp H, Donachie AM, Robson NC, Mowat AM. A role for dendritic cells in the priming of antigen-specific CD4+  and CD8+  T lymphocytes by immune-stimulating complexes in vivo. Int Immunol 2003;15:711-720. 
  82. Golebiewska JE, Wardowska A, Pietrowska M, Wojakowska A, Debska-Slizien A. Small extracellular vesicles in transplant rejection. Cells 2021;10:2989. 
  83. Dietrich J, Menne C, Lauritsen JP, von Essen M, Rasmussen AB, Odum N, Geisler C. Ligand-induced TCR down-regulation is not dependent on constitutive TCR cycling. J Immunol 2002;168:5434-5440. 
  84. Martinez-Martin N, Fernandez-Arenas E, Cemerski S, Delgado P, Turner M, Heuser J, Irvine DJ, Huang B, Bustelo XR, Shaw A, et al. T cell receptor internalization from the immunological synapse is mediated by TC21 and RhoG GTPase-dependent phagocytosis. Immunity 2011;35:208-222. 
  85. von Essen M, Bonefeld CM, Siersma V, Rasmussen AB, Lauritsen JP, Nielsen BL, Geisler C. Constitutive and ligand-induced TCR degradation. J Immunol 2004;173:384-393. 
  86. Huang JF, Yang Y, Sepulveda H, Shi W, Hwang I, Peterson PA, Jackson MR, Sprent J, Cai Z. TCR-mediated internalization of peptide-MHC complexes acquired by T cells. Science 1999;286:952-954. 
  87. Park JS, Kim JH, Soh WC, Lee KS, Kim CH, Chung IJ, Lee S, Kim HR, Jun CD. Trogocytic-molting of T-cell microvilli controls T-cell clonal expansion. bioRxiv. 2022. doi: 10.1101/2022.05.03.490404. 
  88. Lee H, Kim SH, Lee JS, Yang YH, Nam JM, Kim BW, Ko YG. Mitochondrial oxidative phosphorylation complexes exist in the sarcolemma of skeletal muscle. BMB Rep 2016;49:116-121.