Skip to main content

Advertisement

Log in

How to find your way through the thymus: a practical guide for aspiring T cells

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Thymocytes must complete an elaborate developmental program in the thymus to ultimately generate T cells that express functional but neither harmful nor useless TCRs. Each developmental step coincides with dynamic relocation of the thymocytes between anatomically discrete thymic microenvironments, suggesting that thymocytes’ migration is tightly regulated by their developmental status. Chemokines produced by thymic stromal cells and chemokine receptors on the thymocytes play an indispensable role in guiding developing thymocytes into the different microenvironments. In addition to long-range migration, chemokines increase the thymocytes’ motility, enhancing their interaction with stromal cells. During the past several years, much progress has been made to determine the various signals that guide thymocytes on their journey within the thymus. In this review, we summarize the progress in identifying chemokines and other chemoattractant signals that direct intrathymic migration. Furthermore, we discuss the recent advances of two-photon microscopy in determining dynamic motility and interaction behavior of thymocytes within distinct compartments to provide a better understanding of the relationship between thymocyte motility and development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bhakta NR, Oh DY, Lewis RS (2005) Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nat Immunol 6(2):143–151. doi:10.1038/ni1161

    PubMed  CAS  Google Scholar 

  2. Petrie HT, Zúñiga-Pflücker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol 25:649–679. doi:10.1146/annurev.immunol.23.021704.115715

    PubMed  CAS  Google Scholar 

  3. Boehm T, Bleul CC (2006) Thymus-homing precursors and the thymic microenvironment. Trends Immunol 27(10):477–484. doi:10.1016/j.it.2006.08.004

    PubMed  CAS  Google Scholar 

  4. Raviola E, Karnovsky MJ (1972) Evidence for a blood–thymus barrier using electron-opaque tracers. J Exp Med 136(3):466–498

    PubMed  CAS  Google Scholar 

  5. Bousso P, Robey EA (2004) Dynamic behavior of T cells and thymocytes in lymphoid organs as revealed by two-photon microscopy. Immunity 21(3):349–355. doi:10.1016/j.immuni.2004.08.005

    PubMed  CAS  Google Scholar 

  6. Zlotnik A, Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12(2):121–127

    PubMed  CAS  Google Scholar 

  7. Janas ML, Turner M (2010) Stromal cell-derived factor 1α and CXCR4: newly defined requirements for efficient thymic β-selection. Trends Immunol 31(10):370–376. doi:10.1016/j.it.2010.07.002

    PubMed  CAS  Google Scholar 

  8. Petrie RJ, Doyle AD, Yamada KM (2009) Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10(8):538–549. doi:10.1038/nrm2729

    PubMed  CAS  Google Scholar 

  9. Wilkinson PC (1988) Chemotaxis and chemokinesis: confusion about definitions. J Immunol Methods 110(1):143–149

    PubMed  CAS  Google Scholar 

  10. Wilkinson P (1996) Cell locomotion and chemotaxis: basic concepts and methodological approaches. Methods 10(1):74–81

    PubMed  CAS  Google Scholar 

  11. Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133(1):38–52. doi:10.1016/j.cell.2008.03.011

    PubMed  CAS  Google Scholar 

  12. Vergara-Silva A, Schaefer KL, Berg LJ (2002) Compartmentalized Eph receptor and ephrin expression in the thymus. Mech Dev 119(Suppl 1):S225–S229

    PubMed  Google Scholar 

  13. Munoz JJ, Alonso CL, Sacedon R, Crompton T, Vicente A, Jimenez E, Varas A, Zapata AG (2002) Expression and function of the Eph A receptors and their ligands ephrins A in the rat thymus. J Immunol 169(1):177–184

    PubMed  CAS  Google Scholar 

  14. Alfaro D, Garcia-Ceca JJ, Cejalvo T, Jimenez E, Jenkinson EJ, Anderson G, Munoz JJ, Zapata A (2007) EphrinB1-EphB signaling regulates thymocyte-epithelium interactions involved in functional T cell development. Eur J Immunol 37(9):2596–2605. doi:10.1002/eji.200737097

    PubMed  CAS  Google Scholar 

  15. Munoz JJ, Alfaro D, Garcia-Ceca J, Alonso CL, Jimenez E, Zapata A (2006) Thymic alterations in EphA4-deficient mice. J Immunol 177(2):804–813

    PubMed  CAS  Google Scholar 

  16. Yu G, Mao J, Wu Y, Luo H, Wu J (2006) Ephrin-B1 is critical in T-cell development. J Biol Chem 281(15):10222–10229. doi:10.1074/jbc.M510320200

    PubMed  CAS  Google Scholar 

  17. Foster KE, Gordon J, Cardenas K, Veiga-Fernandes H, Makinen T, Grigorieva E, Wilkinson DG, Blackburn CC, Richie E, Manley NR, Adams RH, Kioussis D, Coles MC (2010) EphB-ephrin-B2 interactions are required for thymus migration during organogenesis. Proc Natl Acad Sci USA 107(30):13414–13419. doi:10.1073/pnas.1003747107

    PubMed  CAS  Google Scholar 

  18. Shimoyama M, Matsuoka H, Nagata A, Iwata N, Tamekane A, Okamura A, Gomyo H, Ito M, Jishage K, Kamada N, Suzuki H, Tetsuo Noda T, Matsui T (2002) Developmental expression of EphB6 in the thymus: lessons from EphB6 knockout mice. Biochem Biophys Res Commun 298(1):87–94

    PubMed  CAS  Google Scholar 

  19. Alfaro D, Munoz JJ, Garcia-Ceca J, Cejalvo T, Jimenez E, Zapata AG (2011) The Eph/ephrinB signal balance determines the pattern of T-cell maturation in the thymus. Immunol Cell Biol. doi:10.1038/icb.2010.172

  20. Garcia-Ceca J, Jimenez E, Alfaro D, Cejalvo T, Munoz JJ, Zapata AG (2009) Cell-autonomous role of EphB2 and EphB3 receptors in the thymic epithelial cell organization. Eur J Immunol 39(10):2916–2924. doi:10.1002/eji.200939437

    PubMed  CAS  Google Scholar 

  21. de Wit J, Verhaagen J (2003) Role of semaphorins in the adult nervous system. Prog Neurobiol 71(2–3):249–267. doi:S0301008203001394[pii]

    PubMed  Google Scholar 

  22. Okuno T, Nakatsuji Y, Kumanogoh A (2011) The role of immune semaphorins in multiple sclerosis. FEBS Lett. doi:10.1016/j.febslet.2011.03.033

  23. Takamatsu H, Okuno T, Kumanogoh A (2010) Regulation of immune cell responses by semaphorins and their receptors. Cell Mol Immunol 7(2):83–88. doi:10.1038/cmi.2009.111

    PubMed  Google Scholar 

  24. Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75(7):1389–1399

    PubMed  CAS  Google Scholar 

  25. Kruger RP, Aurandt J, Guan KL (2005) Semaphorins command cells to move. Nat Rev Mol Cell Biol 6(10):789–800

    PubMed  CAS  Google Scholar 

  26. Mendes-da-Cruz DA, Lepelletier Y, Brignier AC, Smaniotto S, Renand A, Milpied P, Dardenne M, Hermine O, Savino W (2009) Neuropilins, semaphorins, and their role in thymocyte development. Ann N Y Acad Sci 1153:20–28. doi:10.1111/j.1749-6632.2008.03980.x

    PubMed  Google Scholar 

  27. Lepelletier Y, Smaniotto S, Hadj-Slimane R, Villa-Verde DM, Nogueira AC, Dardenne M, Hermine O, Savino W (2007) Control of human thymocyte migration by Neuropilin-1/Semaphorin-3A-mediated interactions. Proc Natl Acad Sci USA 104(13):5545–5550. doi:10.1073/pnas.0700705104

    PubMed  CAS  Google Scholar 

  28. Hogg N, Patzak I, Willenbrock F (2011) The insider’s guide to leukocyte integrin signalling and function. Nat Rev Immunol 11(6):416–426. doi:10.1038/nri2986

    PubMed  CAS  Google Scholar 

  29. Woolf E, Grigorova I, Sagiv A, Grabovsky V, Feigelson SW, Shulman Z, Hartmann T, Sixt M, Cyster JG, Alon R (2007) Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Nat Immunol 8(10):1076–1085. doi:10.1038/ni1499

    PubMed  CAS  Google Scholar 

  30. Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R, Sixt M (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453(7191):51–55. doi:10.1038/nature06887

    PubMed  Google Scholar 

  31. Schmeissner PJ, Xie H, Smilenov LB, Shu F, Marcantonio EE (2001) Integrin functions play a key role in the differentiation of thymocytes in vivo. J Immunol 167(7):3715–3724

    PubMed  CAS  Google Scholar 

  32. Arroyo AG, Yang JT, Rayburn H, Hynes RO (1996) Differential requirements for alpha4 integrins during fetal and adult hematopoiesis. Cell 85(7):997–1008

    PubMed  CAS  Google Scholar 

  33. Arroyo AG, Yang JT, Rayburn H, Hynes RO (1999) Alpha4 integrins regulate the proliferation/differentiation balance of multilineage hematopoietic progenitors in vivo. Immunity 11(5):555–566

    PubMed  CAS  Google Scholar 

  34. Schmits R, Kundig TM, Baker DM, Shumaker G, Simard JJ, Duncan G, Wakeham A, Shahinian A, van der Heiden A, Bachmann MF, Ohashi PS, Mak TW, Hickstein DD (1996) LFA-1-deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor. J Exp Med 183(4):1415–1426

    PubMed  CAS  Google Scholar 

  35. Semmrich M, Smith A, Feterowski C, Beer S, Engelhardt B, Busch DH, Bartsch B, Laschinger M, Hogg N, Pfeffer K, Holzmann B (2005) Importance of integrin LFA-1 deactivation for the generation of immune responses. J Exp Med 201(12):1987–1998. doi:10.1084/jem.20041850

    PubMed  CAS  Google Scholar 

  36. Prockop SE, Petrie HT (2004) Functional assessment of alphaEbeta7/E-cadherin interactions in the steady state postnatal thymus. Clin Dev Immunol 11(2):135–141

    PubMed  CAS  Google Scholar 

  37. Bungartz G, Stiller S, Bauer M, Muller W, Schippers A, Wagner N, Fassler R, Brakebusch C (2006) Adult murine hematopoiesis can proceed without beta1 and beta7 integrins. Blood 108(6):1857–1864. doi:10.1182/blood-2005-10-007658

    PubMed  CAS  Google Scholar 

  38. Scharffetter-Kochanek K, Lu H, Norman K, van Nood N, Munoz F, Grabbe S, McArthur M, Lorenzo I, Kaplan S, Ley K, Smith CW, Montgomery CA, Rich S, Beaudet AL (1998) Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med 188(1):119–131

    PubMed  CAS  Google Scholar 

  39. Shier P, Otulakowski G, Ngo K, Panakos J, Chourmouzis E, Christjansen L, Lau CY, Fung-Leung WP (1996) Impaired immune responses toward alloantigens and tumor cells but normal thymic selection in mice deficient in the beta2 integrin leukocyte function-associated antigen-1. J Immunol 157(12):5375–5386

    PubMed  CAS  Google Scholar 

  40. van der Neut R, Krimpenfort P, Calafat J, Niessen CM, Sonnenberg A (1996) Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat Genet 13(3):366–369. doi:10.1038/ng0796-366

    PubMed  Google Scholar 

  41. Xu H, Gonzalo JA, St Pierre Y, Williams IR, Kupper TS, Cotran RS, Springer TA, Gutierrez-Ramos JC (1994) Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med 180(1):95–109

    PubMed  CAS  Google Scholar 

  42. Sligh JE Jr, Ballantyne CM, Rich SS, Hawkins HK, Smith CW, Bradley A, Beaudet AL (1993) Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci USA 90(18):8529–8533

    PubMed  CAS  Google Scholar 

  43. Koni PA, Joshi SK, Temann UA, Olson D, Burkly L, Flavell RA (2001) Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J Exp Med 193(6):741–754

    PubMed  CAS  Google Scholar 

  44. Zlotoff DA, Sambandam A, Logan TD, Bell JJ, Schwarz BA, Bhandoola A (2010) CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood 115(10):1897–1905. doi:10.1182/blood-2009-08-237784

    PubMed  CAS  Google Scholar 

  45. Donskoy E, Goldschneider I (1992) Thymocytopoiesis is maintained by blood-borne precursors throughout postnatal life. A study in parabiotic mice. J Immunol 148(6):1604–1612

    PubMed  CAS  Google Scholar 

  46. Goldschneider I, Komschlies KL, Greiner DL (1986) Studies of thymocytopoiesis in rats and mice I Kinetics of appearance of thymocytes using a direct intrathymic adoptive transfer assay for thymocyte precursors. J Exp Med 163(1):1–17

    PubMed  CAS  Google Scholar 

  47. Scollay R, Smith J, Stauffer V (1986) Dynamics of early T cells: prothymocyte migration and proliferation in the adult mouse thymus. Immunol Rev 91:129–157

    PubMed  CAS  Google Scholar 

  48. Shortman K, Wu L (1996) Early T lymphocyte progenitors. Annu Rev Immunol 14:29–47. doi:10.1146/annurev.immunol.14.1.29

    PubMed  CAS  Google Scholar 

  49. Foss DL, Donskoy E, Goldschneider I (2001) The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J Exp Med 193(3):365–374

    PubMed  CAS  Google Scholar 

  50. Bhandoola A, von Boehmer H, Petrie HT, Zúñiga-Pflücker JC (2007) Commitment and developmental potential of extrathymic and intrathymic T cell precursors: plenty to choose from. Immunity 26(6):678–689. doi:10.1016/j.immuni.2007.05.009

    PubMed  CAS  Google Scholar 

  51. Bell JJ, Bhandoola A (2008) The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 452(7188):764–767. doi:10.1038/nature06840

    PubMed  CAS  Google Scholar 

  52. Allman D, Sambandam A, Kim S, Miller JP, Pagan A, Well D, Meraz A, Bhandoola A (2003) Thymopoiesis independent of common lymphoid progenitors. Nat Immunol 4(2):168–174. doi:10.1038/ni878

    PubMed  CAS  Google Scholar 

  53. Moore MA, Owen JJ (1967) Experimental studies on the development of the thymus. J Exp Med 126(4):715–726

    PubMed  CAS  Google Scholar 

  54. Haynes BF, Heinly CS (1995) Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J Exp Med 181(4):1445–1458

    PubMed  CAS  Google Scholar 

  55. Liu C, Saito F, Liu Z, Lei Y, Uehara S, Love P, Lipp M, Kondo S, Manley N, Takahama Y (2006) Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood 108(8):2531–2539. doi:10.1182/blood-2006-05-024190

    PubMed  CAS  Google Scholar 

  56. Krueger A, Willenzon S, Lyszkiewicz M, Kremmer E, Förster R (2010) CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus. Blood 115(10):1906–1912. doi:10.1182/blood-2009-07-235721

    PubMed  CAS  Google Scholar 

  57. Stimamiglio MA, Jimenez E, Silva-Barbosa SD, Alfaro D, Garcia-Ceca JJ, Munoz JJ, Cejalvo T, Savino W, Zapata A (2010) EphB2-mediated interactions are essential for proper migration of T cell progenitors during fetal thymus colonization. J Leukoc Biol 88(3):483–494. doi:10.1189/jlb.0210079

    PubMed  CAS  Google Scholar 

  58. Rossi FMV, Corbel SY, Merzaban JS, Carlow DA, Gossens K, Duenas J, So L, Yi L, Ziltener HJ (2005) Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat Immunol 6(6):626–634. doi:10.1038/ni1203

    PubMed  CAS  Google Scholar 

  59. Gossens K, Naus S, Corbel SY, Lin S, Rossi FMV, Kast J, Ziltener HJ (2009) Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J Exp Med 206(4):761–778. doi:10.1084/jem.20082502

    PubMed  CAS  Google Scholar 

  60. Scimone ML, Aifantis I, Apostolou I, von Boehmer H, von Andrian UH (2006) A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus. Proc Natl Acad Sci USA 103(18):7006–7011. doi:10.1073/pnas.0602024103

    PubMed  CAS  Google Scholar 

  61. Wu L, Kincade PW, Shortman K (1993) The CD44 expressed on the earliest intrathymic precursor population functions as a thymus homing molecule but does not bind to hyaluronate. Immunol Lett 38(1):69–75

    PubMed  CAS  Google Scholar 

  62. Protin U, Schweighoffer T, Jochum W, Hilberg F (1999) CD44-deficient mice develop normally with changes in subpopulations and recirculation of lymphocyte subsets. J Immunol 163(9):4917–4923

    PubMed  CAS  Google Scholar 

  63. Shortman K, Egerton M, Spangrude GJ, Scollay R (1990) The generation and fate of thymocytes. Semin Immunol 2(1):3–12

    PubMed  CAS  Google Scholar 

  64. Crompton T, Outram SV, Hager-Theodorides AL (2007) Sonic hedgehog signalling in T-cell development and activation. Nat Rev Immunol 7(9):726–735. doi:10.1038/nri2151

    PubMed  CAS  Google Scholar 

  65. Schmitt TM, Zúñiga-Pflücker JC (2002) Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17(6):749–756

    PubMed  CAS  Google Scholar 

  66. Schmitt TM, Ciofani M, Petrie HT, Zúñiga-Pflücker JC (2004) Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions. J Exp Med 200(4):469–479. doi:10.1084/jem.20040394

    PubMed  CAS  Google Scholar 

  67. Tan JB, Visan I, Yuan JS, Guidos CJ (2005) Requirement for Notch1 signals at sequential early stages of intrathymic T cell development. Nat Immunol 6(7):671–679. doi:10.1038/ni1217

    PubMed  CAS  Google Scholar 

  68. Sambandam A, Maillard I, Zediak VP, Xu L, Gerstein RM, Aster JC, Pear WS, Bhandoola A (2005) Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat Immunol 6(7):663–670. doi:10.1038/ni1216

    PubMed  CAS  Google Scholar 

  69. Ciofani M, Zúñiga-Pflücker JC (2005) Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 6(9):881–888. doi:10.1038/ni1234

    PubMed  CAS  Google Scholar 

  70. Plotkin J, Prockop SE, Lepique A, Petrie HT (2003) Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J Immunol 171(9):4521–4527

    PubMed  CAS  Google Scholar 

  71. Trampont PC, Tosello-Trampont A-C, Shen Y, Duley AK, Sutherland AE, Bender TP, Littman DR, Ravichandran KS (2010) CXCR4 acts as a costimulator during thymic beta-selection. Nat Immunol 11(2):162–170. doi:10.1038/ni.1830

    PubMed  CAS  Google Scholar 

  72. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393(6685):595–599. doi:10.1038/31269

    PubMed  CAS  Google Scholar 

  73. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (1998) Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 95(16):9448–9453

    PubMed  CAS  Google Scholar 

  74. Ara T, Itoi M, Kawabata K, Egawa T, Tokoyoda K, Sugiyama T, Fujii N, Amagai T, Nagasawa T (2003) A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J Immunol 170(9):4649–4655

    PubMed  CAS  Google Scholar 

  75. Kawabata K, Ujikawa M, Egawa T, Kawamoto H, Tachibana K, Iizasa H, Katsura Y, Kishimoto T, Nagasawa T (1999) A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc Natl Acad Sci USA 96(10):5663–5667

    PubMed  CAS  Google Scholar 

  76. Egawa T, Kawabata K, Kawamoto H, Amada K, Okamoto R, Fujii N, Kishimoto T, Katsura Y, Nagasawa T (2001) The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor. Immunity 15(2):323–334

    PubMed  CAS  Google Scholar 

  77. Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P, Miazek A, Mattei MG, Malissen M, Jordan BR, Malissen B, Carrier A, Naquet P (2000) The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur J Immunol 30(1):262–271

    PubMed  CAS  Google Scholar 

  78. Misslitz A, Pabst O, Hintzen G, Ohl L, Kremmer E, Petrie HT, Forster R (2004) Thymic T cell development and progenitor localization depend on CCR7. J Exp Med 200(4):481–491

    PubMed  CAS  Google Scholar 

  79. Vicari AP, Figueroa DJ, Hedrick JA, Foster JS, Singh KP, Menon S, Copeland NG, Gilbert DJ, Jenkins NA, Bacon KB, Zlotnik A (1997) TECK: a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development. Immunity 7(2):291–301

    PubMed  CAS  Google Scholar 

  80. Norment AM, Bogatzki LY, Gantner BN, Bevan MJ (2000) Murine CCR9, a chemokine receptor for thymus-expressed chemokine that is up-regulated following pre-TCR signaling. J Immunol 164(2):639–648

    PubMed  CAS  Google Scholar 

  81. Wurbel M-A, Malissen B, Campbell JJ (2006) Complex regulation of CCR9 at multiple discrete stages of T cell development. Eur J Immunol 36(1):73–81. doi:10.1002/eji.200535203

    PubMed  CAS  Google Scholar 

  82. Benz C, Heinzel K, Bleul CC (2004) Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur J Immunol 34(12):3652–3663

    PubMed  CAS  Google Scholar 

  83. Uehara S, Grinberg A, Farber JM, Love PE (2002) A role for CCR9 in T lymphocyte development and migration. J Immunol 168(6):2811–2819

    PubMed  CAS  Google Scholar 

  84. Holländer GA, Wang B, Nichogiannopoulou A, Platenburg PP, van Ewijk W, Burakoff SJ, Gutierrez-Ramos JC, Terhorst C (1995) Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373(6512):350–353. doi:10.1038/373350a0

    PubMed  Google Scholar 

  85. van Ewijk W, Holländer G, Terhorst C, Wang B (2000) Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 127(8):1583–1591

    PubMed  Google Scholar 

  86. Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER (1998) Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci USA 95(20):11822–11827

    PubMed  CAS  Google Scholar 

  87. Robey EA, Bousso P (2003) Visualizing thymocyte motility using 2-photon microscopy. Immunol Rev 195:51–57

    PubMed  Google Scholar 

  88. Ladi E, Yin X, Chtanova T, Robey EA (2006) Thymic microenvironments for T cell differentiation and selection. Nat Immunol 7(4):338–343. doi:10.1038/ni1323

    PubMed  CAS  Google Scholar 

  89. Witt CM, Robey EA (2005) Thymopoiesis in 4 dimensions. Semin Immunol 17(1):95–102. doi:10.1016/j.smim.2004.09.008

    PubMed  CAS  Google Scholar 

  90. Yin X, Chtanova T, Ladi E, Robey EA (2006) Thymocyte motility: mutants, movies and migration patterns. Curr Opin Immunol 18(2):191–197. doi:10.1016/j.coi.2006.02.004

    PubMed  CAS  Google Scholar 

  91. Bhakta NR, Lewis RS (2005) Real-time measurement of signaling and motility during T cell development in the thymus. Semin Immunol 17(6):411–420. doi:10.1016/j.smim.2005.09.004

    PubMed  CAS  Google Scholar 

  92. Bousso P, Bhakta NR, Lewis RS, Robey E (2002) Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296(5574):1876–1880. doi:10.1126/science.1070945

    PubMed  CAS  Google Scholar 

  93. Witt CM, Raychaudhuri S, Schaefer B, Chakraborty AK, Robey EA (2005) Directed migration of positively selected thymocytes visualized in real time. PLoS Biol 3(6):e160

    PubMed  Google Scholar 

  94. Kurobe H, Liu C, Ueno T, Saito F, Ohigashi I, Seach N, Arakaki R, Hayashi Y, Kitagawa T, Lipp M, Boyd RL, Takahama Y (2006) CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24(2):165–177

    PubMed  CAS  Google Scholar 

  95. Ladi E, Schwickert TA, Chtanova T, Chen Y, Herzmark P, Yin X, Aaron H, Chan SW, Lipp M, Roysam B, Robey EA (2008) Thymocyte-dendritic cell interactions near sources of CCR7 ligands in the thymic cortex. J Immunol 181(10):7014–7023

    PubMed  CAS  Google Scholar 

  96. Phee H, Dzhagalov I, Mollenauer M, Wang Y, Irvine DJ, Robey E, Weiss A (2010) Regulation of thymocyte positive selection and motility by GIT2. Nat Immunol 11(6):503–511. doi:10.1038/ni.1868

    PubMed  CAS  Google Scholar 

  97. Turner CE (2000) Paxillin interactions. J Cell Sci 113(Pt 23):4139–4140

    PubMed  CAS  Google Scholar 

  98. Frank SR, Hansen SH (2008) The PIX-GIT complex: a G protein signaling cassette in control of cell shape. Semin Cell Dev Biol 19(3):234–244

    PubMed  CAS  Google Scholar 

  99. Randazzo PA, Inoue H, Bharti S (2007) Arf GAPs as regulators of the actin cytoskeleton. Biol Cell 99(10):583–600

    PubMed  CAS  Google Scholar 

  100. Hoefen RJ, Berk BC (2006) The multifunctional GIT family of proteins. J Cell Sci 119(Pt 8):1469–1475

    PubMed  CAS  Google Scholar 

  101. Sabe H, Onodera Y, Mazaki Y, Hashimoto S (2006) ArfGAP family proteins in cell adhesion, migration and tumor invasion. Curr Opin Cell Biol 18(5):558–564

    PubMed  CAS  Google Scholar 

  102. Vitale N, Patton WA, Moss J, Vaughan M, Lefkowitz RJ, Premont RT (2000) GIT proteins. A novel family of phosphatidylinositol 3, 4, 5-trisphosphate-stimulated GTPase-activating proteins for ARF6. J Biol Chem 275(18):13901–13906

    PubMed  CAS  Google Scholar 

  103. Premont RT, Claing A, Vitale N, Perry SJ, Lefkowitz RJ (2000) The GIT family of ADP-ribosylation factor GTPase-activating proteins functional diversity of GIT2 through alternative splicing. J Biol Chem 275(29):22373–22380

    PubMed  CAS  Google Scholar 

  104. Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M, Inoue J (2005) Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308(5719):248–251

    PubMed  CAS  Google Scholar 

  105. Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D, Tizard R, Cate R, Lo D (1995) Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373(6514):531–536

    PubMed  CAS  Google Scholar 

  106. Laufer TM, DeKoning J, Markowitz JS, Lo D, Glimcher LH (1996) Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex. Nature 383(6595):81–85

    PubMed  CAS  Google Scholar 

  107. Davalos-Misslitz AC, Rieckenberg J, Willenzon S, Worbs T, Kremmer E, Bernhardt G, Forster R (2007) Generalized multi-organ autoimmunity in CCR7-deficient mice. Eur J Immunol 37(3):613–622

    PubMed  CAS  Google Scholar 

  108. Yin X, Ladi E, Chan SW, Li O, Killeen N, Kappes DJ, Robey EA (2007) CCR7 expression in developing thymocytes is linked to the CD4 versus CD8 lineage decision. J Immunol 179(11):7358–7364

    PubMed  CAS  Google Scholar 

  109. Singer A, Adoro S, Park JH (2008) Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev 8(10):788–801

    CAS  Google Scholar 

  110. Suzuki G, Sawa H, Kobayashi Y, Nakata Y, Nakagawa K, Uzawa A, Sakiyama H, Kakinuma S, Iwabuchi K, Nagashima K (1999) Pertussis toxin-sensitive signal controls the trafficking of thymocytes across the corticomedullary junction in the thymus. J Immunol 162(10):5981–5985

    PubMed  CAS  Google Scholar 

  111. Kwan J, Killeen N (2004) CCR7 directs the migration of thymocytes into the thymic medulla. J Immunol 172(7):3999–4007

    PubMed  CAS  Google Scholar 

  112. Ueno T, Saito F, Gray DH, Kuse S, Hieshima K, Nakano H, Kakiuchi T, Lipp M, Boyd RL, Takahama Y (2004) CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J Exp Med 200(4):493–505

    PubMed  CAS  Google Scholar 

  113. Ehrlich LI, Oh DY, Weissman IL, Lewis RS (2009) Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes. Immunity 31(6):986–998

    PubMed  CAS  Google Scholar 

  114. Nitta T, Nitta S, Lei Y, Lipp M, Takahama Y (2009) CCR7-mediated migration of developing thymocytes to the medulla is essential for negative selection to tissue-restricted antigens. Proc Natl Acad Sci USA 106(40):17129–17133

    PubMed  CAS  Google Scholar 

  115. Wurbel MA, Malissen B, Campbell JJ (2006) Complex regulation of CCR9 at multiple discrete stages of T cell development. Eur J Immunol 36(1):73–81

    PubMed  CAS  Google Scholar 

  116. Choi YI, Duke-Cohan JS, Ahmed WB, Handley MA, Mann F, Epstein JA, Clayton LK, Reinherz EL (2008) PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla. Immunity 29(6):888–898

    PubMed  CAS  Google Scholar 

  117. Annunziato F, Romagnani P, Cosmi L, Beltrame C, Steiner BH, Lazzeri E, Raport CJ, Galli G, Manetti R, Mavilia C, Vanini V, Chantry D, Maggi E, Romagnani S (2000) Macrophage-derived chemokine and EBI1-ligand chemokine attract human thymocytes in different stage of development and are produced by distinct subsets of medullary epithelial cells: possible implications for negative selection. J Immunol 165(1):238–246

    PubMed  CAS  Google Scholar 

  118. Chantry D, Romagnani P, Raport CJ, Wood CL, Epp A, Romagnani S, Gray PW (1999) Macrophage-derived chemokine is localized to thymic medullary epithelial cells and is a chemoattractant for CD3(+), CD4(+), CD8(low) thymocytes. Blood 94(6):1890–1898

    PubMed  CAS  Google Scholar 

  119. Baekkevold ES, Wurbel MA, Kivisakk P, Wain CM, Power CA, Haraldsen G, Campbell JJ (2005) A role for CCR4 in development of mature circulating cutaneous T helper memory cell populations. J Exp Med 201(7):1045–1051

    PubMed  CAS  Google Scholar 

  120. Wurbel MA, Malissen M, Guy-Grand D, Meffre E, Nussenzweig MC, Richelme M, Carrier A, Malissen B (2001) Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood 98(9):2626–2632

    PubMed  CAS  Google Scholar 

  121. Wurbel MA, Malissen M, Guy-Grand D, Malissen B, Campbell JJ (2007) Impaired accumulation of antigen-specific CD8 lymphocytes in chemokine CCL25-deficient intestinal epithelium and lamina propria. J Immunol 178(12):7598–7606

    PubMed  CAS  Google Scholar 

  122. Le Borgne M, Ladi E, Dzhagalov I, Herzmark P, Liao YF, Chakraborty AK, Robey EA (2009) The impact of negative selection on thymocyte migration in the medulla. Nat Immunol 10(8):823–830. doi:10.1038/ni.1761

    PubMed  CAS  Google Scholar 

  123. Ansel KM, Cyster JG (2001) Chemokines in lymphopoiesis and lymphoid organ development. Curr Opin Immunol 13(2):172–179

    PubMed  CAS  Google Scholar 

  124. Derbinski J, Kyewski B (2010) How thymic antigen presenting cells sample the body’s self-antigens. Curr Opin Immunol 22(5):592–600. doi:10.1016/j.coi.2010.08.003

    PubMed  CAS  Google Scholar 

  125. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L (2008) Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455(7211):396–400. doi:10.1038/nature07208

    PubMed  CAS  Google Scholar 

  126. Kyewski BA, Fathman CG, Kaplan HS (1984) Intrathymic presentation of circulating non-major histocompatibility complex antigens. Nature 308(5955):196–199

    PubMed  CAS  Google Scholar 

  127. Volkmann A, Zal T, Stockinger B (1997) Antigen-presenting cells in the thymus that can negatively select MHC class II-restricted T cells recognizing a circulating self antigen. J Immunol 158(2):693–706

    PubMed  CAS  Google Scholar 

  128. Baba T, Nakamoto Y, Mukaida N (2009) Crucial contribution of thymic Sirp alpha + conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J Immunol 183(5):3053–3063. doi:10.4049/jimmunol.0900438

    PubMed  CAS  Google Scholar 

  129. Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH (2006) Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol 7(10):1092–1100. doi:10.1038/ni1385

    PubMed  CAS  Google Scholar 

  130. Tykocinski LO, Sinemus A, Kyewski B (2008) The thymus medulla slowly yields its secrets. Ann N Y Acad Sci 1143:105–122. doi:10.1196/annals.1443.018

    PubMed  CAS  Google Scholar 

  131. Aaltonen J, Bjorses P, Sandkuijl L, Perheentupa J, Peltonen L (1994) An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet 8(1):83–87. doi:10.1038/ng0994-83

    PubMed  CAS  Google Scholar 

  132. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17(4):393–398. doi:10.1038/ng1297-393

    PubMed  CAS  Google Scholar 

  133. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self-shadow within the thymus by the Aire protein. Science 298(5597):1395–1401. doi:10.1126/science.1075958

    PubMed  CAS  Google Scholar 

  134. Abramson J, Giraud M, Benoist C, Mathis D (2010) Aire’s partners in the molecular control of immunological tolerance. Cell 140(1):123–135. doi:10.1016/j.cell.2009.12.030

    PubMed  CAS  Google Scholar 

  135. McCaughtry TM, Wilken MS, Hogquist KA (2007) Thymic emigration revisited. J Exp Med 204(11):2513–2520

    PubMed  CAS  Google Scholar 

  136. Klein L, Hinterberger M, Wirnsberger G, Kyewski B (2009) Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev 9(12):833–844

    CAS  Google Scholar 

  137. Ehrlich LIR, Oh DY, Weissman IL, Lewis RS (2009) Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes. Immunity 31(6):986–998. doi:10.1016/j.immuni.2009.09.020

    PubMed  CAS  Google Scholar 

  138. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23(2):227–239

    PubMed  CAS  Google Scholar 

  139. Scollay RG, Butcher EC, Weissman IL (1980) Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10(3):210–218

    PubMed  CAS  Google Scholar 

  140. Hazenberg MD, Borghans JA, de Boer RJ, Miedema F (2003) Thymic output: a bad TREC record. Nat Immunol 4(2):97–99. doi:10.1038/ni0203-97ni0203-97[pii]

    PubMed  CAS  Google Scholar 

  141. Chaffin KE, Beals CR, Wilkie TM, Forbush KA, Simon MI, Perlmutter RM (1990) Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J 9(12):3821–3829

    PubMed  CAS  Google Scholar 

  142. Chaffin KE, Perlmutter RM (1991) A pertussis toxin-sensitive process controls thymocyte emigration. Eur J Immunol 21(10):2565–2573

    PubMed  CAS  Google Scholar 

  143. Chiba K (2005) FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Therapeutics 108(3):308–319

    CAS  Google Scholar 

  144. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427(6972):355–360. doi:10.1038/nature02284

    PubMed  CAS  Google Scholar 

  145. Allende ML, Dreier JL, Mandala S, Proia RL (2004) Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem 279(15):15396–15401

    PubMed  CAS  Google Scholar 

  146. Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, Coughlin SR (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316(5822):295–298

    PubMed  CAS  Google Scholar 

  147. Vogel P, Donoviel MS, Read R, Hansen GM, Hazlewood J, Anderson SJ, Sun W, Swaffield J, Oravecz T (2009) Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions. PloS one 4(1):e4112

    PubMed  Google Scholar 

  148. Zachariah MA, Cyster JG (2010) Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328(5982):1129–1135

    PubMed  CAS  Google Scholar 

  149. Shiow LR, Rosen DB, Brdickova N, Xu Y, An J, Lanier LL, Cyster JG, Matloubian M (2006) CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440(7083):540–544

    PubMed  CAS  Google Scholar 

  150. Carlson CM, Endrizzi BT, Wu J, Ding X, Weinreich MA, Walsh ER, Wani MA, Lingrel JB, Hogquist KA, Jameson SC (2006) Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442(7100):299–302

    PubMed  CAS  Google Scholar 

  151. Fabre S, Carrette F, Chen J, Lang V, Semichon M, Denoyelle C, Lazar V, Cagnard N, Dubart-Kupperschmitt A, Mangeney M, Fruman DA, Bismuth G (2008) FOXO1 regulates L-Selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase. J Immunol 181(5):2980–2989

    PubMed  CAS  Google Scholar 

  152. Barbee SD, Alberola-Ila J (2005) Phosphatidylinositol 3-kinase regulates thymic exit. J Immunol 174(3):1230–1238

    PubMed  CAS  Google Scholar 

  153. Ueno T, Hara K, Willis MS, Malin MA, Hopken UE, Gray DH, Matsushima K, Lipp M, Springer TA, Boyd RL, Yoshie O, Takahama Y (2002) Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16(2):205–218

    PubMed  CAS  Google Scholar 

  154. Vianello F, Kraft P, Mok YT, Hart WK, White N, Poznansky MC (2005) A CXCR4-dependent chemorepellent signal contributes to the emigration of mature single-positive CD4 cells from the fetal thymus. J Immunol 175(8):5115–5125

    PubMed  CAS  Google Scholar 

  155. Srivatsan S, Peng SL (2005) Cutting edge: Foxj1 protects against autoimmunity and inhibits thymocyte egress. J Immunol 175(12):7805–7809

    PubMed  CAS  Google Scholar 

  156. 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

    PubMed  CAS  Google Scholar 

  157. Sakata D, Taniguchi H, Yasuda S, Adachi-Morishima A, Hamazaki Y, Nakayama R, Miki T, Minato N, Narumiya S (2007) Impaired T lymphocyte trafficking in mice deficient in an actin-nucleating protein, mDia1. J Exp Med 204(9):2031–2038

    PubMed  CAS  Google Scholar 

  158. Morley SC, Wang C, Lo WL, Lio CW, Zinselmeyer BH, Miller MJ, Brown EJ, Allen PM (2010) The actin-bundling protein L-plastin dissociates CCR7 proximal signaling from CCR7-induced motility. J Immunol 184(7):3628–3638

    PubMed  CAS  Google Scholar 

  159. Katagiri K, Ohnishi N, Kabashima K, Iyoda T, Takeda N, Shinkai Y, Inaba K, Kinashi T (2004) Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking. Nat Immunol 5(10):1045–1051

    PubMed  CAS  Google Scholar 

  160. Dong Y, Du X, Ye J, Han M, Xu T, Zhuang Y, Tao W (2009) A cell-intrinsic role for Mst1 in regulating thymocyte egress. J Immunol 183(6):3865–3872

    PubMed  CAS  Google Scholar 

  161. Kato S (1997) Thymic microvascular system. Microsc Res Tech 38(3):287–299

    PubMed  CAS  Google Scholar 

  162. Griffith AV, Fallahi M, Nakase H, Gosink M, Young B, Petrie HT (2009) Spatial mapping of thymic stromal microenvironments reveals unique features influencing T lymphoid differentiation. Immunity 31(6):999–1009. doi:10.1016/j.immuni.2009.09.024

    PubMed  CAS  Google Scholar 

  163. Gill J, Malin M, Sutherland J, Gray D, Hollander G, Boyd R (2003) Thymic generation and regeneration. Immunol Rev 195:28–50

    PubMed  CAS  Google Scholar 

  164. van den Brink MRM, Alpdogan O, Boyd RL (2004) Strategies to enhance T-cell reconstitution in immunocompromised patients. Nat Rev Immunol 4(11):856–867. doi:10.1038/nri1484

    PubMed  Google Scholar 

  165. Zlotoff DA, Bhandoola A (2011) Hematopoietic progenitor migration to the adult thymus. Ann NY Acad Sci 1217(1):122–138. doi:10.1111/j.1749-6632.2010.05881.x

    PubMed  CAS  Google Scholar 

  166. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei G-J, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296(5566):346–349. doi:10.1126/science.1070238

    PubMed  CAS  Google Scholar 

  167. Liu G, Yang K, Burns S, Shrestha S, Chi H (2010) The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat Immunol 11(11):1047–1056. doi:10.1038/ni.1939

    PubMed  CAS  Google Scholar 

  168. Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9(11):883–897. doi:10.1038/nrd3248

    PubMed  CAS  Google Scholar 

  169. Calderon L, Boehm T (2011) Three chemokine receptors cooperatively regulate homing of hematopoietic progenitors to the embryonic mouse thymus. Proc Natl Acad Sci U S A 108(18):7517–7522. doi:1016428108 [pii] 10.1073/pnas.1016428108

  170. Janas ML, Varano G, Gudmundsson K, Noda M, Nagasawa T, Turner M (2010) Thymic development beyond beta-selection requires phosphatidylinositol 3-kinase activation by CXCR4. J Exp Med 207(1):247–261. doi:jem.20091430 [pii] 10.1084/jem.20091430

    Google Scholar 

Download references

Acknowledgments

We thank E. Robey, J. Ross, B. Au-Yeung, and A. Limlander for reading the manuscript and providing comments. Supported by Grant Number K01 AR059754-01 from NIAMS (H.P.) and the Cancer Research Institute (I.D.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hyewon Phee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dzhagalov, I., Phee, H. How to find your way through the thymus: a practical guide for aspiring T cells. Cell. Mol. Life Sci. 69, 663–682 (2012). https://doi.org/10.1007/s00018-011-0791-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0791-6

Keywords

Navigation