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Thymus Colonization: Who, How, How Many?

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

De novo generation of T cells depends on continual colonization of the thymus by bone marrow-derived progenitors. Thymus seeding progenitors (TSPs) constitute a heterogeneous population comprising multipotent and lineage-restricted cell types. Entry into the thymic microenvironment is tightly controlled and recent quantitative studies have revealed that the adult murine thymus only contains approximately 160 niches to accommodate TSPs. Of these niches only about 6% are open for seeding on average at steady-state. Here, I review the state of understanding of colonization of the adult murine thymus with a particular focus on past and current controversies in the field. Improving thymus colonization and/or maintaining intact TSP niches during the course of pre-conditioning regimens are likely to be critical for efficient T-cell regeneration after hematopoietic stem cell transplantation.

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References

  • Allman DM, Sambandam A, Kim S et al (2003) Thymopoiesis independent of common lymphoid progenitors. Nat Immunol 4:168–174

    Article  CAS  PubMed  Google Scholar 

  • Buono M, Facchini R, Matsuoka S et al (2016) A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat Cell Biol 18:157–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casero D, Sandoval S, Seet CS et al (2015) Long non-coding RNA profiling of human lymphoid progenitor cells reveals transcriptional divergence of B cell and T cell lineages. Nat Immunol 16:1282–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaudhry MS, Velardi E, Dudakov JA et al (2016) Thymus: the next (re)generation. Immunol Rev 271:56–71

    Article  CAS  PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Ezine S, Weissman IL, Rouse RV (1984) Bone marrow cells give rise to distinct cell clones within the thymus. Nature 309:629–631

    Article  CAS  PubMed  Google Scholar 

  • Feyerabend TB, Terszowski G, Tietz A et al (2009) Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms. Immunity 30:67–79

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foss D, Donskoy E, Goldschneider I (2002) Functional demonstration of intrathymic binding sites and microvascular gates for prothymocytes in irradiated mice. Int Immunol 14:331–338

    Article  CAS  PubMed  Google Scholar 

  • 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 163:1–17

    Article  CAS  PubMed  Google Scholar 

  • Gossens K, Naus S, Corbel SY et al (2009) Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J Exp Med 206:761–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham VA, Marzo AL, Tough DF (2007) A role for CD44 in T cell development and function during direct competition between CD44+ and CD44− cells. Eur J Immunol 37:925–934

    Article  CAS  PubMed  Google Scholar 

  • Haddad R, Guimiot F, Six EM et al (2006) Dynamics of thymus-colonizing cells during human development. Immunity 24:217–230

    Article  CAS  PubMed  Google Scholar 

  • Kadish JL, Basch RS (1976) Hematopoietic thymocyte precursors. I. Assay and kinetics of the appearance of progeny. J Exp Med 143:1082–1099

    Article  CAS  PubMed  Google Scholar 

  • Kawamoto H, Katsura Y (2009) A new paradigm for hematopoietic cell lineages: revision of the classical concept of the myeloid-lymphoid dichotomy. Trends Immunol 30:193–200

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krueger A, Willenzon S, Lyszkiewicz M et al (2010) CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus. Blood 115:1906–1912

    Article  CAS  PubMed  Google Scholar 

  • Krueger A, Zietara N, Łyszkiewicz M (2017) T cell development by the numbers. Trends Immunol 38:128–139

    Article  CAS  PubMed  Google Scholar 

  • Laurenti E, Doulatov S, Zandi S et al (2013) The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment. Nat Immunol 14:756–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lind EF, Prockop SE, Porritt HE et al (2001) Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med 194:127–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu M, Kawamoto H, Katsube Y et al (2002) The common myelolymphoid progenitor: a key intermediate stage in hemopoiesis generating T and B cells. J Immunol 169:3519–3525

    Article  CAS  PubMed  Google Scholar 

  • Luc S, Luis TC, Boukarabila H et al (2012) The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential. Nat Immunol 13:412–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lucas B, James KD, Cosway EJ et al (2016) Lymphotoxin β receptor controls T cell progenitor entry to the thymus. J Immunol 197:2665–2672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Łyszkiewicz M, Zietara N, Föhse L et al (2015) Limited niche availability suppresses murine intrathymic dendritic-cell development from noncommitted progenitors. Blood 125:457–464

    Article  PubMed  Google Scholar 

  • Martin C, Aifantis I, Scimone ML et al (2003) Efficient thymic immigration of B220 + lymphoid-restricted bone marrow cells with T precursor potential. Nat Immunol 4:866–873

    Article  CAS  PubMed  Google Scholar 

  • Martins VC, Ruggiero E, Schlenner SM et al (2012) Thymus-autonomous T cell development in the absence of progenitor import. J Exp Med 209:1409–1417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martins VC, Busch K, Juraeva D et al (2014) Cell competition is a tumour suppressor mechanism in the thymus. Nature 509:465–470

    Article  CAS  PubMed  Google Scholar 

  • Mori S, Shortman K, Wu L (2001) Characterization of thymus-seeding precursor cells from mouse bone marrow. Blood 98:696–704

    Article  CAS  PubMed  Google Scholar 

  • Peaudecerf L, Lemos S, Galgano A et al (2012) Thymocytes may persist and differentiate without any input from bone marrow progenitors. J Exp Med 209:1401–1408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Porritt HE, Gordon KM, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prockop SE, Petrie HT (2004) Regulation of thymus size by competition for stromal niches among early T cell progenitors. J Immunol 173:1604–1611

    Article  CAS  PubMed  Google Scholar 

  • Rossi FMV, Corbel SY, Merzaban JS et al (2005) Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat Immunol 6:626–634

    Article  CAS  PubMed  Google Scholar 

  • Saran N, Łyszkiewicz M, Pommerencke J et al (2010) Multiple extrathymic precursors contribute to T-cell development with different kinetics. Blood 115:1137–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlenner SM, Rodewald HR (2010) Early T cell development and the pitfalls of potential. Trends Immunol 31:303–310

    Article  CAS  PubMed  Google Scholar 

  • Schlenner SM, Madan V, Busch K et al (2010) Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus. Immunity 32:426–436

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Scimone ML, Aifantis I, Apostolou I et al (2006) A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus. Proc Natl Acad Sci USA 103:7006–7011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Serwold T, Ehrlich LIR, Weissman IL (2009) Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis. Blood 113:807–815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi Y, Wu W, Chai Q et al (2016) LTβR controls thymic portal endothelial cells for haematopoietic progenitor cell homing and T-cell regeneration. Nat Commun 7:12369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shultz LD, Brehm MA, Garcia-Martinez JV et al (2012) Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12:786–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Six EM, Bonhomme D, Monteiro M et al (2007) A human postnatal lymphoid progenitor capable of circulating and seeding the thymus. J Exp Med 204:3085–3093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Svensson M, Marsal J, Uronen-Hansson H et al (2008) Involvement of CCR9 at multiple stages of adult T lymphopoiesis. J Leukoc Biol 83:156–164

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Umland O, Mwangi WN, Anderson BM et al (2007) The blood contains multiple distinct progenitor populations with clonogenic B and T lineage potential. J Immunol 178:4147–4152

    Article  CAS  PubMed  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

    Article  CAS  PubMed  Google Scholar 

  • 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 38:69–75

    Article  CAS  PubMed  Google Scholar 

  • Zhang SL, Wang X, Manna S et al (2014) Chemokine treatment rescues profound T-lineage progenitor homing defect after bone marrow transplant conditioning in mice. Blood 124:296–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zietara N, Łyszkiewicz M, Puchałka J et al (2015) Multicongenic fate mapping quantification of dynamics of thymus colonization. J Exp Med 212:1589–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zlotoff DA, Sambandam A, Logan TD et al (2010) CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood 115:1897–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zlotoff DA, Zhang SL, De Obaldia ME et al (2011) Delivery of progenitors to the thymus limits T-lineage reconstitution after bone marrow transplantation. Blood 118:1962–1970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft) (KR2320/3-1, KR2320/5-1, SFB902-B15, and EXC62 “REBIRTH”).

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  1. Institute for Molecular Medicine, Goethe University Frankfurt am Main, 60590, Frankfurt am Main, Germany

    Andreas Krueger

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  1. Andreas Krueger
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Correspondence to Andreas Krueger.

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Krueger, A. Thymus Colonization: Who, How, How Many?. Arch. Immunol. Ther. Exp. 66, 81–88 (2018). https://doi.org/10.1007/s00005-017-0503-5

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  • DOI: https://doi.org/10.1007/s00005-017-0503-5

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