Skip to main content
SpringerLink
Log in

Trafficking to the Thymus

  • Chapter
  • First Online:
Thymic Development and Selection of T Lymphocytes

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

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.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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 102:13586–13591

    PubMed  CAS  Google Scholar 

  • 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 15:659–669

    PubMed  CAS  Google Scholar 

  • 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 121:295–306

    PubMed  CAS  Google Scholar 

  • 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 4:168–174

    PubMed  CAS  Google Scholar 

  • 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 107:2453–2460

    PubMed  CAS  Google Scholar 

  • 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 362:70–73

    PubMed  CAS  Google Scholar 

  • 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 138:186–197

    PubMed  CAS  Google Scholar 

  • 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 470:90–94

    CAS  Google Scholar 

  • Bell JJ, Bhandoola A (2008) The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 452:764–767

    PubMed  CAS  Google Scholar 

  • 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 64:591–604

    PubMed  CAS  Google Scholar 

  • 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 205:1187–1199

    PubMed  CAS  Google Scholar 

  • 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 41:55–62

    PubMed  CAS  Google Scholar 

  • 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 187:1839–1848

    PubMed  CAS  Google Scholar 

  • 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 26:678–689

    PubMed  CAS  Google Scholar 

  • 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 103:3102–3110

    PubMed  CAS  Google Scholar 

  • Boehm T, Bleul CC (2006) Thymus-homing precursors and the thymic microenvironment. Trends Immunol 27:477–484

    PubMed  CAS  Google Scholar 

  • Boehm T, Bleul CC, Schorpp M (2003) Genetic dissection of thymus development in mouse and zebrafish. Immunol Rev 195:15–27

    PubMed  CAS  Google Scholar 

  • 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 201:1307–1318

    PubMed  CAS  Google Scholar 

  • 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 108:7517–7522

    PubMed  CAS  Google Scholar 

  • Calderon L, Boehm T (2012) Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell 149:159–172

    PubMed  CAS  Google Scholar 

  • 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 105:886–893

    PubMed  CAS  Google Scholar 

  • 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 118:2723–2732

    Google Scholar 

  • 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 98:14541–14546

    PubMed  CAS  Google Scholar 

  • Christensen JL, Wright DE, Wagers AJ, Weissman IL (2004) Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol 2:E75

    PubMed  Google Scholar 

  • Chung B, Barbara-Burnham L, Barsky L, Weinberg K (2001) Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 98:1601–1606

    PubMed  CAS  Google Scholar 

  • Ciofani M, Zuniga-Pflucker JC (2007) The thymus as an inductive site for T lymphopoiesis. Annu Rev Cell Dev Biol 23:463–493

    PubMed  CAS  Google Scholar 

  • 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 109:3579–3587

    PubMed  CAS  Google Scholar 

  • De Obaldia ME, Bell JJ, Bhandoola A (2013) Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus. Blood 121:64–71

    PubMed  Google Scholar 

  • 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 96:14493–14498

    PubMed  CAS  Google Scholar 

  • 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 36:288–297

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 171:3568–3575

    PubMed  CAS  Google Scholar 

  • 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 396:690–695

    PubMed  CAS  Google Scholar 

  • 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 336:91–95

    PubMed  CAS  Google Scholar 

  • 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 25:992–1004

    PubMed  CAS  Google Scholar 

  • 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 93:2234–2243

    PubMed  CAS  Google Scholar 

  • Flores KG, Li J, Sempowski GD, Haynes BF, Hale LP (1999) Analysis of the human thymic perivascular space during aging. J Clin Invest 104:1031–1039

    PubMed  CAS  Google Scholar 

  • 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 104:2794–2800

    PubMed  CAS  Google Scholar 

  • 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 175:4363–4373

    PubMed  CAS  Google Scholar 

  • 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 119:2478–2488

    PubMed  CAS  Google Scholar 

  • Goodman JW, Hodgson GS (1962) Evidence for stem cells in the peripheral blood of mice. Blood 19:702–714

    PubMed  CAS  Google Scholar 

  • 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 206:761–778

    PubMed  CAS  Google Scholar 

  • 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 11:169–177

    PubMed  Google Scholar 

  • 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 459:796–801

    PubMed  CAS  Google Scholar 

  • 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 115:930–939

    PubMed  CAS  Google Scholar 

  • Haynes L, Swain SL (2006) Why aging T cells fail: implications for vaccination. Immunity 24:663–666

    PubMed  CAS  Google Scholar 

  • Hess I, Boehm T (2012) Intravital imaging of thymopoiesis reveals dynamic lympho-epithelial interactions. Immunity 36:298–309

    PubMed  CAS  Google Scholar 

  • Hilfer SR, Brown JW (1984) The development of pharyngeal endocrine organs in mouse and chick embryos. Scan Electron Microsc 4:2009–2022

    Google Scholar 

  • 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 122:4716–4726

    PubMed  CAS  Google Scholar 

  • 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 205:2507–2513

    PubMed  CAS  Google Scholar 

  • 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

  • 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 17:117–130

    PubMed  CAS  Google Scholar 

  • 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 103:530–537

    PubMed  CAS  Google Scholar 

  • 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 23:2376–2381

    PubMed  CAS  Google Scholar 

  • Iwasaki H, Akashi K (2007) Hematopoietic developmental pathways: on cellular basis. Oncogene 26:6687–6696

    PubMed  CAS  Google Scholar 

  • Izon DJ (2008) T-cell development: thymus-settling progenitors: settled? Immunol Cell Biol 86:552–553

    PubMed  CAS  Google Scholar 

  • Jin Y, Wu MX (2008) Requirement of Galphai in thymic homing and early T cell development. Mol Immunol 45:3401–3410

    PubMed  CAS  Google Scholar 

  • 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 138:1026–1030

    PubMed  CAS  Google Scholar 

  • 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 12:441–450

    PubMed  CAS  Google Scholar 

  • 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 111:5734–5744

    PubMed  CAS  Google Scholar 

  • 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 205:523–531

    PubMed  CAS  Google Scholar 

  • 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 97:1534–1542

    PubMed  CAS  Google Scholar 

  • 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 111:1147–1156

    PubMed  CAS  Google Scholar 

  • Koch U, Radtke F (2011) Mechanisms of T cell development and transformation. Annu Rev Cell Dev Biol 27:539–562

    PubMed  CAS  Google Scholar 

  • Kondo M, Weissman IL, Akashi K (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91:661–672

    PubMed  CAS  Google Scholar 

  • Krueger A, von Boehmer H (2007) Identification of a T lineage-committed progenitor in adult blood. Immunity 26:105–116

    PubMed  CAS  Google Scholar 

  • Krueger A, Garbe AI, von Boehmer H (2006) Phenotypic plasticity of T cell progenitors upon exposure to Notch ligands. J Exp Med 203:1977–1984

    PubMed  CAS  Google Scholar 

  • 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 115:1906–1912

    PubMed  CAS  Google Scholar 

  • Kunisaki Y, Frenette PS (2012) The secrets of the bone marrow niche: Enigmatic niche brings challenge for HSC expansion. Nat Med 18:864–865

    PubMed  CAS  Google Scholar 

  • 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 104:6311–6316

    PubMed  CAS  Google Scholar 

  • Lei Y, Liu C, Saito F, Fukui Y, Takahama Y (2009) Role of DOCK2 and DOCK180 in fetal thymus colonization. Eur J Immunol 39:2695–2702

    PubMed  CAS  Google Scholar 

  • 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 111:187–196

    PubMed  CAS  Google Scholar 

  • 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 271:3255–3264

    PubMed  CAS  Google Scholar 

  • Li J, Iwanami N, Hoa VQ, Furutani-Seiki M, Takahama Y (2007) Noninvasive intravital imaging of thymocyte dynamics in medaka. J Immunol 179:1605–1615

    PubMed  CAS  Google Scholar 

  • 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 11:663–675

    PubMed  CAS  Google Scholar 

  • 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 194:127–134

    PubMed  CAS  Google Scholar 

  • 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 95:3025–3031

    PubMed  CAS  Google Scholar 

  • 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 108:2531–2539

    PubMed  CAS  Google Scholar 

  • 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 175:5848–5856

    PubMed  CAS  Google Scholar 

  • 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 38:203–214

    PubMed  Google Scholar 

  • 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 13:412–419

    PubMed  CAS  Google Scholar 

  • Lymperi S, Ferraro F, Scadden DT (2010) The HSC niche concept has turned 31. Has our knowledge matured? Ann N Y Acad Sci 1192:12–18

    PubMed  CAS  Google Scholar 

  • 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 332:143–149

    PubMed  CAS  Google Scholar 

  • 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 156:4609–4616

    PubMed  CAS  Google Scholar 

  • Maillard I, Fang T, Pear WS (2005) Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol 23:945–974

    PubMed  CAS  Google Scholar 

  • 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 115:2601–2609

    Google Scholar 

  • 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 193:429–444

    PubMed  CAS  Google Scholar 

  • 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 75:1715–1720

    PubMed  CAS  Google Scholar 

  • 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 4:866–873

    PubMed  CAS  Google Scholar 

  • 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 209:1409–1417

    PubMed  CAS  Google Scholar 

  • 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 24:4052–4060

    PubMed  CAS  Google Scholar 

  • 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 466:829–834

    PubMed  CAS  Google Scholar 

  • Mikkola HK, Orkin SH (2006) The journey of developing hematopoietic stem cells. Development 133:3733–3744

    PubMed  CAS  Google Scholar 

  • 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 112:785–792

    Google Scholar 

  • 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 99:4592–4600

    PubMed  CAS  Google Scholar 

  • Min H, Montecino-Rodriguez E, Dorshkind K (2004) Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol 173:245–250

    PubMed  CAS  Google Scholar 

  • 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 200:481–491

    PubMed  CAS  Google Scholar 

  • Morris GP, Allen PM (2012) How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat Immunol 13:121–128

    PubMed  CAS  Google Scholar 

  • Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL (1997) Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–1939

    PubMed  CAS  Google Scholar 

  • Muller AM, Medvinsky A, Strouboulis J, Grosveld F, Dzierzak E (1994) Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1:291–301

    PubMed  CAS  Google Scholar 

  • Munoz JJ, Cejalvo T, Alonso-Colmenar LM, Alfaro D, Garcia-Ceca J, Zapata A (2011) Eph/Ephrin-mediated interactions in the thymus. NeuroImmunoModulation 18:271–280

    PubMed  CAS  Google Scholar 

  • 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 26:207–216

    PubMed  CAS  Google Scholar 

  • Olsen NJ, Watson MB, Henderson GS, Kovacs WJ (1991) Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice. Endocrinology 129:2471–2476

    PubMed  CAS  Google Scholar 

  • Osawa M, Hanada K, Hamada H, Nakauchi H (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273:242–245

    PubMed  CAS  Google Scholar 

  • Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52

    PubMed  CAS  Google Scholar 

  • 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 209:1401–1408

    PubMed  CAS  Google Scholar 

  • 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 103:110–119

    PubMed  CAS  Google Scholar 

  • Perry SS, Welner RS, Kouro T, Kincade PW, Sun XH (2006) Primitive lymphoid progenitors in bone marrow with T lineage reconstituting potential. J Immunol 177:2880–2887

    PubMed  CAS  Google Scholar 

  • 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 3:687–694

    PubMed  CAS  Google Scholar 

  • 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 14:125–130

    PubMed  CAS  Google Scholar 

  • 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 4:62–72

    PubMed  CAS  Google Scholar 

  • 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 198:957–962

    PubMed  CAS  Google Scholar 

  • 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 20:735–745

    PubMed  CAS  Google Scholar 

  • 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 99:6228–6233

    PubMed  CAS  Google Scholar 

  • 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 24:976–985

    PubMed  CAS  Google Scholar 

  • 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 34:308–319

    PubMed  CAS  Google Scholar 

  • 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 173:6098–6108

    PubMed  CAS  Google Scholar 

  • 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 13:4229–4240

    PubMed  CAS  Google Scholar 

  • 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 102:9194–9199

    PubMed  CAS  Google Scholar 

  • 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 6:626–634

    PubMed  CAS  Google Scholar 

  • Rothenberg EV (2012) Transcriptional drivers of the T-cell lineage program. Curr Opin Immunol 24:132–138

    PubMed  CAS  Google Scholar 

  • Ruiz P, Wiles MV, Imhof BA (1995) Alpha 6 integrins participate in pro-T cell homing to the thymus. Eur J Immunol 25:2034–2041

    PubMed  CAS  Google Scholar 

  • Schwarz BA, Bhandoola A (2004) Circulating hematopoietic progenitors with T lineage potential. Nat Immunol 5:953–960

    PubMed  CAS  Google Scholar 

  • Schwarz BA, Sambandam A, Maillard I, Harman BC, Love PE, Bhandoola A (2007) Selective thymus settling regulated by cytokine and chemokine receptors. J Immunol 178:2008–2017

    PubMed  CAS  Google Scholar 

  • 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 103:7006–7011

    PubMed  CAS  Google Scholar 

  • 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 113:807–815

    PubMed  CAS  Google Scholar 

  • Shortman K, Wu L (1996) Early T lymphocyte progenitors. Annu Rev Immunol 14:29–47

    PubMed  CAS  Google Scholar 

  • 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 80:388–395

    PubMed  CAS  Google Scholar 

  • 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 93:467–480

    PubMed  CAS  Google Scholar 

  • Spangrude GJ, Scollay R (1990) Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes. Kinetics and phenotype of progeny. J Immunol 145:3661–3668

    PubMed  CAS  Google Scholar 

  • Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241:58–62

    PubMed  CAS  Google Scholar 

  • Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314

    PubMed  CAS  Google Scholar 

  • 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 88:483–494

    PubMed  CAS  Google Scholar 

  • 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 89:91–92

    PubMed  CAS  Google Scholar 

  • 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 34:829–830

    PubMed  CAS  Google Scholar 

  • Stritesky GL, Jameson SC, Hogquist KA (2012) Selection of self-reactive T cells in the thymus. Annu Rev Immunol 30:95–114

    PubMed  CAS  Google Scholar 

  • 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 188:4385–4393

    PubMed  CAS  Google Scholar 

  • 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 122:795–801

    PubMed  CAS  Google Scholar 

  • 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 23:350–359

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 200:493–505

    PubMed  CAS  Google Scholar 

  • 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-S83

    Google Scholar 

  • 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 7:291–301

    PubMed  CAS  Google Scholar 

  • Vicente R, Adjali O, Jacquet C, Zimmermann VS, Taylor N (2010) Intrathymic transplantation of bone marrow-derived progenitors provides long-term thymopoiesis. Blood 115:1913–1920

    PubMed  CAS  Google Scholar 

  • Wallis VJ, Leuchars E, Chwalinski S, Davies AJ (1975) On the sparse seeding of bone marrow and thymus in radiation chimaeras. Transplantation 19:2–11

    PubMed  CAS  Google Scholar 

  • 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 97:1458–1466

    PubMed  CAS  Google Scholar 

  • Weinreich MA, Hogquist KA (2008) Thymic emigration: when and how T cells leave home. J Immunol 181:2265–2270

    PubMed  CAS  Google Scholar 

  • Williams KM, Lucas PJ, Bare CV, Wang J, Chu YW, Tayler E, Kapoor V, Gress RE (2008) CCL25 increases thymopoiesis after androgen withdrawal. Blood 112:3255–3263

    PubMed  CAS  Google Scholar 

  • 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 2:279–285

    PubMed  CAS  Google Scholar 

  • 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 28:2025–2034

    PubMed  CAS  Google Scholar 

  • 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 178:3551–3557

    PubMed  CAS  Google Scholar 

  • 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 96:1846–1854

    PubMed  Google Scholar 

  • 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 135:1118–1129

    PubMed  CAS  Google Scholar 

  • 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 26:1594–1601

    PubMed  CAS  Google Scholar 

  • Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL (2001) Physiological migration of hematopoietic stem and progenitor cells. Science 294:1933–1936

    PubMed  CAS  Google Scholar 

  • 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 30:262–271

    PubMed  CAS  Google Scholar 

  • 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 205:711–723

    PubMed  CAS  Google Scholar 

  • 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 133:2041–2051

    PubMed  CAS  Google Scholar 

  • 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 12:1039–1047

    PubMed  CAS  Google Scholar 

  • Zediak VP, Maillard I, Bhandoola A (2007) Multiple prethymic defects underlie age-related loss of T progenitor competence. Blood 110:1161–1167

    PubMed  CAS  Google Scholar 

  • Zlotoff DA, Bhandoola A (2011) Hematopoietic progenitor migration to the adult thymus. Ann N Y Acad Sci 1217:122–138

    PubMed  CAS  Google Scholar 

  • 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 115:1897–1905

    PubMed  CAS  Google Scholar 

  • 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 118:1962–1970

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 264 John Morgan Building 3620 Hamilton Walk, Philadelphia, PA, USA

    Shirley L. Zhang & Avinash Bhandoola

Authors
  1. Shirley L. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Avinash Bhandoola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Avinash Bhandoola .

Editor information

Editors and Affiliations

  1. Department of Developmental Immunology, Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany

    Thomas Boehm

  2. Institute for Genome Research, Division of Experimental Immunology, University of Tokushima, Tokushima, Japan

    Yousuke Takahama

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Zhang, S.L., Bhandoola, A. (2013). Trafficking to the Thymus. In: Boehm, T., Takahama, Y. (eds) Thymic Development and Selection of T Lymphocytes. Current Topics in Microbiology and Immunology, vol 373. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2013_324

Download citation

Publish with us

Policies and ethics

Search

Navigation