Thymic Development and Selection of T Lymphocytes pp 87-111

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 373)

Trafficking to the Thymus

Chapter

Abstract

The continuous production of T lymphocytes requires that hematopoietic progenitors developing in the bone marrow migrate to the thymus. Rare progenitors egress from the bone marrow into the circulation, then traffic via the blood to the thymus. It is now evident that thymic settling is tightly regulated by selectin ligands, chemokine receptors, and integrins, among other factors. Identification of these signals has enabled progress in identifying specific populations of hematopoietic progenitors that can settle the thymus. Understanding the nature of progenitor cells and the molecular mechanisms involved in thymic settling may allow for therapeutic manipulation of this process, and improve regeneration of the T lineage in patients with impaired T cell numbers.

References

  1. Adjali O, Vicente RR, Ferrand C, Jacquet C, Mongellaz C, Tiberghien P, Chebli K, Zimmermann VS, Taylor N (2005) Intrathymic administration of hematopoietic progenitor cells enhances T cell reconstitution in ZAP-70 severe combined immunodeficiency. Proc Natl Acad Sci U S A 102:13586–13591PubMedGoogle Scholar
  2. Adolfsson J, Borge OJ, Bryder D, Theilgaard-Monch K, Astrand-Grundstrom I, Sitnicka E, Sasaki Y, Jacobsen SE (2001) Upregulation of Flt3 Expression within the bone marrow Lin(-)Sca1(+)c- kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15:659–669PubMedGoogle Scholar
  3. Adolfsson J, Mansson R, Buza-Vidas N, Hultquist A, Liuba K, Jensen CT, Bryder D, Yang L, Borge OJ, Thoren LA, Anderson K, Sitnicka E, Sasaki Y, Sigvardsson M, Jacobsen SE (2005) Identification of Flt3 + lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121:295–306PubMedGoogle Scholar
  4. 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 4:168–174PubMedGoogle Scholar
  5. Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL, Gray DH, Feinman J, Kochman AA, Eng JM, Suh D, Muriglan SJ, Boyd RL, van den Brink MR (2006) Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 107:2453–2460PubMedGoogle Scholar
  6. Anderson G, Jenkinson EJ, Moore NC, Owen JJ (1993) MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362:70–73PubMedGoogle Scholar
  7. Bajoghli B, Aghaallaei N, Hess I, Rode I, Netuschil N, Tay BH, Venkatesh B, Yu JK, Kaltenbach SL, Holland ND, Diekhoff D, Happe C, Schorpp M, Boehm T (2009) Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates. Cell 138:186–197PubMedGoogle Scholar
  8. Bajoghli B, Guo P, Aghaallaei N, Hirano M, Strohmeier C, McCurley N, Bockman DE, Schorpp M, Cooper MD, Boehm T (2011) A thymus candidate in lampreys. Nature 470:90–94Google Scholar
  9. Bell JJ, Bhandoola A (2008) The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 452:764–767PubMedGoogle Scholar
  10. Belyaev NN, Biro J, Athanasakis D, Fernandez-Reyes D, Potocnik AJ (2012) Global transcriptional analysis of primitive thymocytes reveals accelerated dynamics of T cell specification in fetal stages. Immunogenetics 64:591–604PubMedGoogle Scholar
  11. Benz C, Martins VC, Radtke F, Bleul CC (2008) The stream of precursors that colonizes the thymus proceeds selectively through the early T lineage precursor stage of T cell development. J Exp Med 205:1187–1199PubMedGoogle Scholar
  12. Berger M, Figari O, Bruno B, Raiola A, Dominietto A, Fiorone M, Podesta M, Tedone E, Pozzi S, Fagioli F, Madon E, Bacigalupo A (2008) Lymphocyte subsets recovery following allogeneic bone marrow transplantation (BMT): CD4 + cell count and transplant-related mortality. Bone Marrow Transplant 41:55–62PubMedGoogle Scholar
  13. Berzins SP, Boyd RL, Miller JF (1998) The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J Exp Med 187:1839–1848PubMedGoogle Scholar
  14. Bhandoola A, von Boehmer H, Petrie HT, Zuniga-Pflucker JC (2007) Commitment and developmental potential of extrathymic and intrathymic T cell precursors: plenty to choose from. Immunity 26:678–689PubMedGoogle Scholar
  15. Blais ME, Gerard G, Martinic MM, Roy-Proulx G, Zinkernagel RM, Perreault C (2004) Do thymically and strictly extrathymically developing T cells generate similar immune responses? Blood 103:3102–3110PubMedGoogle Scholar
  16. Boehm T, Bleul CC (2006) Thymus-homing precursors and the thymic microenvironment. Trends Immunol 27:477–484PubMedGoogle Scholar
  17. Boehm T, Bleul CC, Schorpp M (2003) Genetic dissection of thymus development in mouse and zebrafish. Immunol Rev 195:15–27PubMedGoogle Scholar
  18. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, Liles WC, Li X, Graham-Evans B, Campbell TB, Calandra G, Bridger G, Dale DC, Srour EF (2005) Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 201:1307–1318PubMedGoogle Scholar
  19. 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 108:7517–7522PubMedGoogle Scholar
  20. Calderon L, Boehm T (2012) Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell 149:159–172PubMedGoogle Scholar
  21. Chen X, Barfield R, Benaim E, Leung W, Knowles J, Lawrence D, Otto M, Shurtleff SA, Neale GA, Behm FG, Turner V, Handgretinger R (2005) Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients. Blood 105:886–893PubMedGoogle Scholar
  22. Chi AW, Chavez A, Xu L, Weber BN, Shestova O, Schaffer A, Wertheim G, Pear WS, Izon D, Bhandoola A (2010) Identification of Flt3(+)CD150(-) myeloid progenitors in adult mouse bone marrow that harbor T lymphoid developmental potential. Blood 118:2723–2732Google Scholar
  23. Christensen JL, Weissman IL (2001) Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci U S A 98:14541–14546PubMedGoogle Scholar
  24. Christensen JL, Wright DE, Wagers AJ, Weissman IL (2004) Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol 2:E75PubMedGoogle Scholar
  25. Chung B, Barbara-Burnham L, Barsky L, Weinberg K (2001) Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 98:1601–1606PubMedGoogle Scholar
  26. Ciofani M, Zuniga-Pflucker JC (2007) The thymus as an inductive site for T lymphopoiesis. Annu Rev Cell Dev Biol 23:463–493PubMedGoogle Scholar
  27. Dallas MH, Varnum-Finney B, Martin PJ, Bernstein ID (2007) Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1. Blood 109:3579–3587PubMedGoogle Scholar
  28. De Obaldia ME, Bell JJ, Bhandoola A (2013) Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus. Blood 121:64–71PubMedGoogle Scholar
  29. Dejbakhsh-Jones S, Strober S (1999) Identification of an early T cell progenitor for a pathway of T cell maturation in the bone marrow. Proc Natl Acad Sci U S A 96:14493–14498PubMedGoogle Scholar
  30. den Braber I, Mugwagwa T, Vrisekoop N, Westera L, Mögling R, de Boer AB, Willems N, Schrijver EH, Spierenburg G, Gaiser K, Mul E, Otto SA, Ruiter AF, Ackermans MT, Miedema F, Borghans JA, de Boer RJ, Tesselaar K (2012) Maintenance of peripheral naive T cells: a mouse-main divide. Immunity 36:288–297Google Scholar
  31. Donskoy E, Goldschneider I (1992) Thymocytopoiesis is maintained by blood-borne precursors throughout postnatal life. A study in parabiotic mice. J Immunol 148:1604–1612PubMedGoogle Scholar
  32. Donskoy E, Foss D, Goldschneider I (2003) Gated importation of prothymocytes by adult mouse thymus is coordinated with their periodic mobilization from bone marrow. J Immunol 171:3568–3575PubMedGoogle Scholar
  33. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695PubMedGoogle Scholar
  34. Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, West ML, Smith OM, Holland AM, Tsai JJ, Boyd RL, van den Brink MR (2012) Interleukin-22 drives endogenous thymic regeneration in mice. Science 336:91–95PubMedGoogle Scholar
  35. Dulude G, Brochu S, Fontaine P, Baron C, Gyger M, Roy DC, Perreault C (1997) Thymic and extrathymic differentiation and expansion of T lymphocytes following bone marrow transplantation in irradiated recipients. Exp Hematol 25:992–1004PubMedGoogle Scholar
  36. Dunon D, Allioli N, Vainio O, Ody C, Imhof BA (1999) Quantification of T-cell progenitors during ontogeny: thymus colonization depends on blood delivery of progenitors. Blood 93:2234–2243PubMedGoogle Scholar
  37. Flores KG, Li J, Sempowski GD, Haynes BF, Hale LP (1999) Analysis of the human thymic perivascular space during aging. J Clin Invest 104:1031–1039PubMedGoogle Scholar
  38. Fry TJ, Sinha M, Milliron M, Chu YW, Kapoor V, Gress RE, Thomas E, Mackall CL (2004) Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood 104:2794–2800PubMedGoogle Scholar
  39. Garcia-Ojeda ME, Dejbakhsh-Jones S, Chatterjea-Matthes D, Mukhopadhyay A, BitMansour A, Weissman IL, Brown JM, Strober S (2005) Stepwise development of committed progenitors in the bone marrow that generate functional T cells in the absence of the thymus. J Immunol 175:4363–4373PubMedGoogle Scholar
  40. Golan K, Vagima Y, Ludin A, Itkin T, Cohen-Gur S, Kalinkovich A, Kollet O, Kim C, Schajnovitz A, Ovadya Y, Lapid K, Shivtiel S, Morris AJ, Ratajczak MZ, Lapidot T (2012) S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release. Blood 119:2478–2488PubMedGoogle Scholar
  41. Goodman JW, Hodgson GS (1962) Evidence for stem cells in the peripheral blood of mice. Blood 19:702–714PubMedGoogle Scholar
  42. Gossens K, Naus S, Corbel SY, Lin S, Rossi FM, 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 206:761–778PubMedGoogle Scholar
  43. Griffith AV, Fallahi M, Venables T, Petrie HT (2011) Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell 11:169–177PubMedGoogle Scholar
  44. Guo P, Hirano M, Herrin BR, Li J, Yu C, Sadlonova A, Cooper MD (2009) Dual nature of the adaptive immune system in lampreys. Nature 459:796–801PubMedGoogle Scholar
  45. Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, Odom J, Vance BA, Christensen BL, Mackall CL, Gress RE (2005) Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 115:930–939PubMedGoogle Scholar
  46. Haynes L, Swain SL (2006) Why aging T cells fail: implications for vaccination. Immunity 24:663–666PubMedGoogle Scholar
  47. Hess I, Boehm T (2012) Intravital imaging of thymopoiesis reveals dynamic lympho-epithelial interactions. Immunity 36:298–309PubMedGoogle Scholar
  48. Hilfer SR, Brown JW (1984) The development of pharyngeal endocrine organs in mouse and chick embryos. Scan Electron Microsc 4:2009–2022Google Scholar
  49. Holland AM, Zakrzewski JL, Tsai JJ, Hanash AM, Dudakov JA, Smith OM, West ML, Singer NV, Brill J, Sun JC, van den Brink MR (2012) Extrathymic development of murine T cells after bone marrow transplantation. J Clin Invest 122:4716–4726PubMedGoogle Scholar
  50. Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T, Ando K, Zuklys S, Hollander GA, Shima DT, Habu S (2008) Delta-like 4 is indispensable in thymic environment specific for T cell development. J Exp Med 205:2507–2513PubMedGoogle Scholar
  51. Hsieh MY, Hong WH, Lin JJ, Lee WI, Lin KL, Wang HS, Chen SH, Yang CP, Jaing TH, Huang JL (2012) T-cell receptor excision circles and repertoire diversity in children with profound T-cell immunodeficiency. J Microbiol Immunol Infect. http://dx.doi.org/10.1016/j.jmii.2012.06.003
  52. Igarashi H, Gregory SC, Yokota T, Sakaguchi N, Kincade PW (2002) Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17:117–130PubMedGoogle Scholar
  53. Ikawa T, Masuda K, Lu M, Minato N, Katsura Y, Kawamoto H (2004) Identification of the earliest prethymic T-cell progenitors in murine fetal blood. Blood 103:530–537PubMedGoogle Scholar
  54. Inlay MA, Bhattacharya D, Sahoo D, Serwold T, Seita J, Karsunky H, Plevritis SK, Dill DL, Weissman IL (2009) Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development. Genes Dev 23:2376–2381PubMedGoogle Scholar
  55. Iwasaki H, Akashi K (2007) Hematopoietic developmental pathways: on cellular basis. Oncogene 26:6687–6696PubMedGoogle Scholar
  56. Izon DJ (2008) T-cell development: thymus-settling progenitors: settled? Immunol Cell Biol 86:552–553PubMedGoogle Scholar
  57. Jin Y, Wu MX (2008) Requirement of Galphai in thymic homing and early T cell development. Mol Immunol 45:3401–3410PubMedGoogle Scholar
  58. Jotereau F, Heuze F, Salomon-Vie V, Gascan H (1987) Cell kinetics in the fetal mouse thymus: precursor cell input, proliferation, and emigration. J Immunol 138:1026–1030PubMedGoogle Scholar
  59. Kawamoto H, Ikawa T, Ohmura K, Fujimoto S, Katsura Y (2000) T cell progenitors emerge earlier than B cell progenitors in the murine fetal liver. Immunity 12:441–450PubMedGoogle Scholar
  60. Kelly RM, Highfill SL, Panoskaltsis-Mortari A, Taylor PA, Boyd RL, Hollander GA, Blazar BR (2008) Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation. Blood 111:5734–5744PubMedGoogle Scholar
  61. Kenins L, Gill JW, Boyd RL, Hollander GA, Wodnar-Filipowicz A (2008) Intrathymic expression of Flt3 ligand enhances thymic recovery after irradiation. J Exp Med 205:523–531PubMedGoogle Scholar
  62. King AG, Horowitz D, Dillon SB, Levin R, Farese AM, MacVittie TJ, Pelus LM (2001) Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta. Blood 97:1534–1542PubMedGoogle Scholar
  63. Kissa K, Murayama E, Zapata A, Cortes A, Perret E, Machu C, Herbomel P (2008) Live imaging of emerging hematopoietic stem cells and early thymus colonization. Blood 111:1147–1156PubMedGoogle Scholar
  64. Koch U, Radtke F (2011) Mechanisms of T cell development and transformation. Annu Rev Cell Dev Biol 27:539–562PubMedGoogle Scholar
  65. Kondo M, Weissman IL, Akashi K (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91:661–672PubMedGoogle Scholar
  66. Krueger A, von Boehmer H (2007) Identification of a T lineage-committed progenitor in adult blood. Immunity 26:105–116PubMedGoogle Scholar
  67. Krueger A, Garbe AI, von Boehmer H (2006) Phenotypic plasticity of T cell progenitors upon exposure to Notch ligands. J Exp Med 203:1977–1984PubMedGoogle Scholar
  68. Krueger A, Willenzon S, Lyszkiewicz M, Kremmer E, Forster R (2010) CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus. Blood 115:1906–1912PubMedGoogle Scholar
  69. Kunisaki Y, Frenette PS (2012) The secrets of the bone marrow niche: Enigmatic niche brings challenge for HSC expansion. Nat Med 18:864–865PubMedGoogle Scholar
  70. Lai AY, Kondo M (2007) Identification of a bone marrow precursor of the earliest thymocytes in adult mouse. Proc Natl Acad Sci U S A 104:6311–6316PubMedGoogle Scholar
  71. Lei Y, Liu C, Saito F, Fukui Y, Takahama Y (2009) Role of DOCK2 and DOCK180 in fetal thymus colonization. Eur J Immunol 39:2695–2702PubMedGoogle Scholar
  72. Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ (2003) Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 111:187–196PubMedGoogle Scholar
  73. Li F, Wilkins PP, Crawley S, Weinstein J, Cummings RD, McEver RP (1996) Post-translational modifications of recombinant P-selectin glycoprotein ligand-1 required for binding to P- and E-selectin. J Biol Chem 271:3255–3264PubMedGoogle Scholar
  74. Li J, Iwanami N, Hoa VQ, Furutani-Seiki M, Takahama Y (2007) Noninvasive intravital imaging of thymocyte dynamics in medaka. J Immunol 179:1605–1615PubMedGoogle Scholar
  75. Li Z, Lan Y, He W, Chen D, Wang J, Zhou F, Wang Y, Sun H, Chen X, Xu C, Li S, Pang Y, Zhang G, Yang L, Zhu L, Fan M, Shang A, Ju Z, Luo L, Ding Y, Guo W, Yuan W, Yang X, Liu B (2012) Mouse embryonic head as a site for hematopoietic stem cell development. Cell Stem Cell 11:663–675PubMedGoogle Scholar
  76. Lind EF, Prockop SE, Porritt HE, Petrie HT (2001) Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med 194:127–134PubMedGoogle Scholar
  77. Liu F, Poursine-Laurent J, Link DC (2000) Expression of the G-CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G-CSF. Blood 95:3025–3031PubMedGoogle Scholar
  78. 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 108:2531–2539PubMedGoogle Scholar
  79. Lu M, Tayu R, Ikawa T, Masuda K, Matsumoto I, Mugishima H, Kawamoto H, Katsura Y (2005) The earliest thymic progenitors in adults are restricted to T, NK, and dendritic cell lineage and have a potential to form more diverse TCRbeta chains than fetal progenitors. J Immunol 175:5848–5856PubMedGoogle Scholar
  80. Lu IN, Chiang BL, Lou KL, Huang PT, Yao CC, Wang JS, Lin LD, Jeng JH, Chang BE (2012) Cloning, expression and characterization of CCL21 and CCL25 chemokines in zebrafish. Dev Comp Immunol 38:203–214PubMedGoogle Scholar
  81. Luc S, Luis TC, Boukarabila H, Macaulay IC, Buza-Vidas N, Bouriez-Jones T, Lutteropp M, Woll PS, Loughran SJ, Mead AJ, Hultquist A, Brown J, Mizukami T, Matsuoka S, Ferry H, Anderson K, Duarte S, Atkinson D, Soneji S, Domanski A, Farley A, Sanjuan-Pla A, Carella C, Patient R, de Bruijn M, Enver T, Nerlov C, Blackburn C, Godin I, Jacobsen SE (2012) The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential. Nat Immunol 13:412–419PubMedGoogle Scholar
  82. Lymperi S, Ferraro F, Scadden DT (2010) The HSC niche concept has turned 31. Has our knowledge matured? Ann N Y Acad Sci 1192:12–18PubMedGoogle Scholar
  83. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, Horowitz ME, Magrath IT, Shad AT, Steinberg SM et al (1995) Age, thymopoiesis, and CD4 + T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 332:143–149PubMedGoogle Scholar
  84. Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE (1996) Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 156:4609–4616PubMedGoogle Scholar
  85. Maillard I, Fang T, Pear WS (2005) Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol 23:945–974PubMedGoogle Scholar
  86. Mansson R, Zandi S, Welinder E, Tsapogas P, Sakaguchi N, Bryder D, Sigvardsson M (2011) Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity. Blood 115:2601–2609Google Scholar
  87. Marchalonis JJ, Schluter SF (1998) A stochastic model for the rapid emergence of specific vertebrate immunity incorporating horizontal transfer of systems enabling duplication and combinational diversification. J Theor Biol 193:429–444PubMedGoogle Scholar
  88. Marshall E, Woolford LB, Lord BI (1997) Continuous infusion of macrophage inflammatory protein MIP-1alpha enhances leucocyte recovery and haemopoietic progenitor cell mobilization after cyclophosphamide. Br J Cancer 75:1715–1720PubMedGoogle Scholar
  89. Martin CH, Aifantis I, Scimone ML, von Andrian UH, Reizis B, von Boehmer H, Gounari F (2003) Efficient thymic immigration of B220+lymphoid-restricted bone marrow cells with T precursor potential. Nat Immunol 4:866–873PubMedGoogle Scholar
  90. Martins VC, Ruggiero E, Schlenner SM, Madan V, Schmidt M, Fink PJ, von Kalle C, Rodewald HR (2012) Thymus-autonomous T cell development in the absence of progenitor import. J Exp Med 209:1409–1417PubMedGoogle Scholar
  91. Masuda K, Kubagawa H, Ikawa T, Chen CC, Kakugawa K, Hattori M, Kageyama R, Cooper MD, Minato N, Katsura Y, Kawamoto H (2005) Prethymic T-cell development defined by the expression of paired immunoglobulin-like receptors. EMBO J 24:4052–4060PubMedGoogle Scholar
  92. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–834PubMedGoogle Scholar
  93. Mikkola HK, Orkin SH (2006) The journey of developing hematopoietic stem cells. Development 133:3733–3744PubMedGoogle Scholar
  94. Miller JP, Doak SMA, Cross AM (1963) Role of the Thymus in Recovery of the Immune Mechanism in the Irradiated Adult Mouse. Exp Biol Med 112:785–792Google Scholar
  95. Min D, Taylor PA, Panoskaltsis-Mortari A, Chung B, Danilenko DM, Farrell C, Lacey DL, Blazar BR, Weinberg KI (2002) Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 99:4592–4600PubMedGoogle Scholar
  96. Min H, Montecino-Rodriguez E, Dorshkind K (2004) Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol 173:245–250PubMedGoogle Scholar
  97. 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 200:481–491PubMedGoogle Scholar
  98. Morris GP, Allen PM (2012) How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat Immunol 13:121–128PubMedGoogle Scholar
  99. Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL (1997) Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–1939PubMedGoogle Scholar
  100. Muller AM, Medvinsky A, Strouboulis J, Grosveld F, Dzierzak E (1994) Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1:291–301PubMedGoogle Scholar
  101. Munoz JJ, Cejalvo T, Alonso-Colmenar LM, Alfaro D, Garcia-Ceca J, Zapata A (2011) Eph/Ephrin-mediated interactions in the thymus. NeuroImmunoModulation 18:271–280PubMedGoogle Scholar
  102. Murray LJ, Luens KM, Estrada MF, Bruno E, Hoffman R, Cohen RL, Ashby MA, Vadhan-Raj S (1998) Thrombopoietin mobilizes CD34+cell subsets into peripheral blood and expands multilineage progenitors in bone marrow of cancer patients with normal hematopoiesis. Exp Hematol 26:207–216PubMedGoogle Scholar
  103. Olsen NJ, Watson MB, Henderson GS, Kovacs WJ (1991) Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice. Endocrinology 129:2471–2476PubMedGoogle Scholar
  104. Osawa M, Hanada K, Hamada H, Nakauchi H (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273:242–245PubMedGoogle Scholar
  105. Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52PubMedGoogle Scholar
  106. Peaudecerf L, Lemos S, Galgano A, Krenn G, Vasseur F, Di Santo JP, Ezine S, Rocha B (2012) Thymocytes may persist and differentiate without any input from bone marrow progenitors. J Exp Med 209:1401–1408PubMedGoogle Scholar
  107. Pelus LM, Bian H, King AG, Fukuda S (2004) Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GRObeta/CXCL2 and GRObetaT/CXCL2delta4. Blood 103:110–119PubMedGoogle Scholar
  108. Perry SS, Welner RS, Kouro T, Kincade PW, Sun XH (2006) Primitive lymphoid progenitors in bone marrow with T lineage reconstituting potential. J Immunol 177:2880–2887PubMedGoogle Scholar
  109. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T (2002) G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 3:687–694PubMedGoogle Scholar
  110. Pettengell R, Woll PJ, Chang J, Coutinho L, Testa NG, Crowther D (1994) Effects of erythropoietin on mobilisation of haemopoietic progenitor cells. Bone Marrow Transplant 14:125–130PubMedGoogle Scholar
  111. Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM (2009) Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 4:62–72PubMedGoogle Scholar
  112. Porritt HE, Gordon K, Petrie HT (2003) Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J Exp Med 198:957–962PubMedGoogle Scholar
  113. Porritt HE, Rumfelt LL, Tabrizifard S, Schmitt TM, Zuniga-Pflucker JC, Petrie HT (2004) Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity 20:735–745PubMedGoogle Scholar
  114. Pruijt JF, Verzaal P, van Os R, de Kruijf EJ, van Schie ML, Mantovani A, Vecchi A, Lindley IJ, Willemze R, Starckx S, Opdenakker G, Fibbe WE (2002) Neutrophils are indispensable for hematopoietic stem cell mobilization induced by interleukin-8 in mice. Proc Natl Acad Sci U S A 99:6228–6233PubMedGoogle Scholar
  115. Ratajczak MZ, Lee H, Wysoczynski M, Wan W, Marlicz W, Laughlin MJ, Kucia M, Janowska-Wieczorek A, Ratajczak J (2010) Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia 24:976–985PubMedGoogle Scholar
  116. Robertson P, Means TK, Luster AD, Scadden DT (2006) CXCR4 and CCR5 mediate homing of primitive bone marrow-derived hematopoietic cells to the postnatal thymus. Exp Hematol 34:308–319PubMedGoogle Scholar
  117. Roden AC, Moser MT, Tri SD, Mercader M, Kuntz SM, Dong H, Hurwitz AA, McKean DJ, Celis E, Leibovich BC, Allison JP, Kwon ED (2004) Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol 173:6098–6108PubMedGoogle Scholar
  118. Rodewald HR, Kretzschmar K, Takeda S, Hohl C, Dessing M (1994) Identification of pro-thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization. EMBO J 13:4229–4240PubMedGoogle Scholar
  119. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL (2005a) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102:9194–9199PubMedGoogle Scholar
  120. Rossi FM, Corbel SY, Merzaban JS, Carlow DA, Gossens K, Duenas J, So L, Yi L, Ziltener HJ (2005b) Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat Immunol 6:626–634PubMedGoogle Scholar
  121. Rothenberg EV (2012) Transcriptional drivers of the T-cell lineage program. Curr Opin Immunol 24:132–138PubMedGoogle Scholar
  122. Ruiz P, Wiles MV, Imhof BA (1995) Alpha 6 integrins participate in pro-T cell homing to the thymus. Eur J Immunol 25:2034–2041PubMedGoogle Scholar
  123. Schwarz BA, Bhandoola A (2004) Circulating hematopoietic progenitors with T lineage potential. Nat Immunol 5:953–960PubMedGoogle Scholar
  124. Schwarz BA, Sambandam A, Maillard I, Harman BC, Love PE, Bhandoola A (2007) Selective thymus settling regulated by cytokine and chemokine receptors. J Immunol 178:2008–2017PubMedGoogle Scholar
  125. 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 U S A 103:7006–7011PubMedGoogle Scholar
  126. Serwold T, Ehrlich LI, Weissman IL (2009) Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis. Blood 113:807–815PubMedGoogle Scholar
  127. Shortman K, Wu L (1996) Early T lymphocyte progenitors. Annu Rev Immunol 14:29–47PubMedGoogle Scholar
  128. Simmons PJ, Masinovsky B, Longenecker BM, Berenson R, Torok-Storb B, Gallatin WM (1992) Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells. Blood 80:388–395PubMedGoogle Scholar
  129. Small TN, Papadopoulos EB, Boulad F, Black P, Castro-Malaspina H, Childs BH, Collins N, Gillio A, George D, Jakubowski A, Heller G, Fazzari M, Kernan N, MacKinnon S, Szabolcs P, Young JW, O’Reilly RJ (1999) Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 93:467–480PubMedGoogle Scholar
  130. Spangrude GJ, Scollay R (1990) Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes. Kinetics and phenotype of progeny. J Immunol 145:3661–3668PubMedGoogle Scholar
  131. Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241:58–62PubMedGoogle Scholar
  132. Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314PubMedGoogle Scholar
  133. 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 88:483–494PubMedGoogle Scholar
  134. Storek J, Douek DC, Keesey JC, Boehmer L, Storer B, Maloney DG (2003) Low T cell receptor excision circle levels in patients thymectomized 25–54 years ago. Immunol Lett 89:91–92PubMedGoogle Scholar
  135. Storek J, Staver JH, Porter BA, Maloney DG (2004) The thymus is typically small at 1 year after autologous or allogeneic T-cell-replete hematopoietic cell transplantation into adults. Bone Marrow Transplant 34:829–830PubMedGoogle Scholar
  136. Stritesky GL, Jameson SC, Hogquist KA (2012) Selection of self-reactive T cells in the thymus. Annu Rev Immunol 30:95–114PubMedGoogle Scholar
  137. Sultana DA, Zhang SL, Todd SP, Bhandoola A (2012) Expression of functional P-selectin glycoprotein ligand 1 on hematopoietic progenitors is developmentally regulated. J Immunol 188:4385–4393PubMedGoogle Scholar
  138. Svaldi M, Lanthaler AJ, Dugas M, Lohse P, Pescosta N, Straka C, Mitterer M (2003) T-cell receptor excision circles: a novel prognostic parameter for the outcome of transplantation in multiple myeloma patients. Br J Haematol 122:795–801PubMedGoogle Scholar
  139. Thompson PK, Zuniga-Pflucker JC (2011) On becoming a T cell, a convergence of factors kick it up a Notch along the way. Semin Immunol 23:350–359PubMedGoogle Scholar
  140. Uehara S, Grinberg A, Farber JM, Love PE (2002) A role for CCR9 in T lymphocyte development and migration. J Immunol 168:2811–2819PubMedGoogle Scholar
  141. 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 200:493–505PubMedGoogle Scholar
  142. van Den Brink M, Leen AM, Baird K, Merchant M, Mackall C, Bollard CM (2013) Enhancing Immune Reconstitution: from Bench to Bedside. Biol Blood Marrow Transplant 19:S79-S83Google Scholar
  143. 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 7:291–301PubMedGoogle Scholar
  144. Vicente R, Adjali O, Jacquet C, Zimmermann VS, Taylor N (2010) Intrathymic transplantation of bone marrow-derived progenitors provides long-term thymopoiesis. Blood 115:1913–1920PubMedGoogle Scholar
  145. Wallis VJ, Leuchars E, Chwalinski S, Davies AJ (1975) On the sparse seeding of bone marrow and thymus in radiation chimaeras. Transplantation 19:2–11PubMedGoogle Scholar
  146. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, Koup RA, Betts MR, Collins RH, Douek DC (2001) Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 97:1458–1466PubMedGoogle Scholar
  147. Weinreich MA, Hogquist KA (2008) Thymic emigration: when and how T cells leave home. J Immunol 181:2265–2270PubMedGoogle Scholar
  148. Williams KM, Lucas PJ, Bare CV, Wang J, Chu YW, Tayler E, Kapoor V, Gress RE (2008) CCL25 increases thymopoiesis after androgen withdrawal. Blood 112:3255–3263PubMedGoogle Scholar
  149. Williams KM, Mella H, Lucas PJ, Williams JA, Telford W, Gress RE (2009) Single cell analysis of complex thymus stromal cell populations: rapid thymic epithelia preparation characterizes radiation injury. Clin Transl Sci 2:279–285PubMedGoogle Scholar
  150. Willimann K, Legler DF, Loetscher M, Roos RS, Delgado MB, Clark-Lewis I, Baggiolini M, Moser B (1998) The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur J Immunol 28:2025–2034PubMedGoogle Scholar
  151. Wils EJ, Braakman E, Verjans GM, Rombouts EJ, Broers AE, Niesters HG, Wagemaker G, Staal FJ, Lowenberg B, Spits H, Cornelissen JJ (2007) Flt3 ligand expands lymphoid progenitors prior to recovery of thymopoiesis and accelerates T cell reconstitution after bone marrow transplantation. J Immunol 178:3551–3557PubMedGoogle Scholar
  152. Wils EJ, van der Holt B, Broers AE, Posthumus-van Sluijs SJ, Gratama JW, Braakman E, Cornelissen JJ (2011) Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients. Haematologica 96:1846–1854PubMedGoogle Scholar
  153. Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, Offner S, Dunant CF, Eshkind L, Bockamp E, Lio P, Macdonald HR, Trumpp A (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135:1118–1129PubMedGoogle Scholar
  154. Winkler IG, Pettit AR, Raggatt LJ, Jacobsen RN, Forristal CE, Barbier V, Nowlan B, Cisterne A, Bendall LJ, Sims NA, Levesque JP (2012) Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation. Leukemia 26:1594–1601PubMedGoogle Scholar
  155. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL (2001) Physiological migration of hematopoietic stem and progenitor cells. Science 294:1933–1936PubMedGoogle Scholar
  156. 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 30:262–271PubMedGoogle Scholar
  157. Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA (2008) Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med 205:711–723PubMedGoogle Scholar
  158. Yokota T, Huang J, Tavian M, Nagai Y, Hirose J, Zuniga-Pflucker JC, Peault B, Kincade PW (2006) Tracing the first waves of lymphopoiesis in mice. Development 133:2041–2051PubMedGoogle Scholar
  159. Zakrzewski JL, Kochman AA, Lu SX, Terwey TH, Kim TD, Hubbard VM, Muriglan SJ, Suh D, Smith OM, Grubin J, Patel N, Chow A, Cabrera-Perez J, Radhakrishnan R, Diab A, Perales MA, Rizzuto G, Menet E, Pamer EG, Heller G, Zuniga-Pflucker JC, Alpdogan O, van den Brink MR (2006) Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med 12:1039–1047PubMedGoogle Scholar
  160. Zediak VP, Maillard I, Bhandoola A (2007) Multiple prethymic defects underlie age-related loss of T progenitor competence. Blood 110:1161–1167PubMedGoogle Scholar
  161. Zlotoff DA, Bhandoola A (2011) Hematopoietic progenitor migration to the adult thymus. Ann N Y Acad Sci 1217:122–138PubMedGoogle Scholar
  162. 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 115:1897–1905PubMedGoogle Scholar
  163. Zlotoff DA, Zhang SL, De Obaldia ME, Hess PR, Todd SP, Logan TD, Bhandoola A (2011) Delivery of progenitors to the thymus limits T-lineage reconstitution after bone marrow transplantation. Blood 118:1962–1970PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicinePerelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA

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