Skip to main content

Advertisement

SpringerLink
Log in

Human intrathymic development: a selective approach

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Human T lymphocytes can be generated from CD34 progenitor cells from different sources. This can be obtained in an in vivo model wherein human thymic tissue and fetal liver is transplanted in an immunodeficient mouse. However, human T cells are also generated in immunodeficient mice without co-transplantation of human thymus or in in vitro hybrid human–mouse fetal thymus organ culture. This shows that xenogeneic mouse thymus tissue supports human T cell differentiation. Finally, human T cells are generated on co-culture with murine stromal cells that express the Delta-like1 ligand for the Notch receptor. How these different environments influence the human T cell repertoire is reviewed and discussed.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Touraine JL, Roncarolo MG, Royo C et al (1987) Fetal tissue transplantation, bone marrow transplantation and prospective gene therapy in severe immunodeficiencies and enzyme deficiencies. Thymus 10:75–87

    PubMed  CAS  Google Scholar 

  2. Hong R, Schulte-Wissermann H, Horowitz SD (1979) Thymic transplantation for relief of immunodeficiency diseases. Surg Clin North Am 59:299–312

    PubMed  CAS  Google Scholar 

  3. Fischer A (2007) Human primary immunodeficiency diseases. Immunity 27:835–845. doi:10.1016/j.immuni.2007.11.012

    Article  PubMed  CAS  Google Scholar 

  4. Editorial (2008) Assessing the status of human immunology. Nat Immunol 9:569

    Article  CAS  Google Scholar 

  5. Payne KJ, Crooks GM (2007) Immune-cell lineage commitment: translation from mice to humans. Immunity 26:674–677 . doi:10.1016/j.immuni.2007.05.011

    Article  PubMed  CAS  Google Scholar 

  6. McCune JM, Namikawa R, Kaneshima H et al (1988) The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 241:1632–1639. doi:10.1126/science.2971269

    Article  PubMed  CAS  Google Scholar 

  7. Fisher AG, Larsson L, Goff LK et al (1990) Human thymocyte development in mouse organ cultures. Int Immunol 2:571–578. doi:10.1093/intimm/2.6.571

    Article  PubMed  CAS  Google Scholar 

  8. Plum J, De Smedt M, Defresne MP et al (1994) Human CD34+ fetal liver stem cells differentiate to T cells in a mouse thymic microenvironment. Blood 84:1587–1593

    PubMed  CAS  Google Scholar 

  9. 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. doi:10.1016/S1074-7613(02)00474-0

    Article  PubMed  CAS  Google Scholar 

  10. La Motte-Mohs RN, Herer E, Zuniga-Pflucker JC (2005) Induction of T-cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro. Blood 105:1431–1439. doi:10.1182/blood-2004-04-1293

    Article  PubMed  CAS  Google Scholar 

  11. Lanier LL, Allison JP, Phillips JH (1986) Correlation of cell surface antigen expression on human thymocytes by multi-color flow cytometric analysis: implications for differentiation. J Immunol 137:2501–2507

    PubMed  CAS  Google Scholar 

  12. Dik WA, Pike-Overzet K, Weerkamp F et al (2005) New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling. J Exp Med 201:1715–1723. doi:10.1084/jem.20042524

    Article  PubMed  CAS  Google Scholar 

  13. Vanhecke D, Leclercq G, Plum J et al (1995) Characterization of distinct stages during the differentiation of human CD69+CD3+ thymocytes and identification of thymic emigrants. J Immunol 155:1862–1872

    PubMed  CAS  Google Scholar 

  14. Vanhecke D, Verhasselt B, De Smedt M et al (1997) MHC class II molecules are required for initiation of positive selection but not during terminal differentiation of human CD4 single positive thymocytes. J Immunol 158:3730–3737

    PubMed  CAS  Google Scholar 

  15. Vanhecke D, Verhasselt B, De Smedt M et al (1997) Human thymocytes become lineage committed at an early postselection CD69+ stage, before the onset of functional maturation. J Immunol 159:5973–5983

    PubMed  CAS  Google Scholar 

  16. Starr TK, Jameson SC, Hogquist KA (2003) Positive and negative selection of T cells. Annu Rev Immunol 21:139–176. doi:10.1146/annurev.immunol.21.120601.141107

    Article  PubMed  CAS  Google Scholar 

  17. Goldrath AW, Bogatzki LY, Bevan MJ (2000) Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med 192:557–564. doi:10.1084/jem.192.4.557

    Article  PubMed  CAS  Google Scholar 

  18. Sandberg JK, Franksson L, Sundback J et al (2000) T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity. J Immunol 165:25–33

    PubMed  CAS  Google Scholar 

  19. Viret C, Wong FS, Janeway CA Jr (1999) Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. Immunity 10:559–568. doi:10.1016/S1074-7613(00)80055-2

    Article  PubMed  CAS  Google Scholar 

  20. Ernst B, Lee DS, Chang JM et al (1999) The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11:173–181. doi:10.1016/S1074-7613(00)80092-8

    Article  PubMed  CAS  Google Scholar 

  21. Hemmer B, Pinilla C, Gran B et al (2000) Contribution of individual amino acids within MHC molecule or antigenic peptide to TCR ligand potency. J Immunol 164:861–871

    PubMed  CAS  Google Scholar 

  22. Mason D (1998) A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 19:395–404. doi:10.1016/S0167-5699(98)01299-7

    Article  PubMed  CAS  Google Scholar 

  23. Bouneaud C, Kourilsky P, Bousso P (2000) Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13:829–840. doi:10.1016/S1074-7613(00)00080-7

    Article  PubMed  CAS  Google Scholar 

  24. Romero P, Dunbar PR, Valmori D et al (1998) Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J Exp Med 188:1641–1650. doi:10.1084/jem.188.9.1641

    Article  PubMed  CAS  Google Scholar 

  25. Coulie PG, Brichard V, Van Pel A et al (1994) A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 180:35–42. doi:10.1084/jem.180.1.35

    Article  PubMed  CAS  Google Scholar 

  26. Kawakami Y, Eliyahu S, Delgado CH et al (1994) Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci USA 91:6458–6462. doi:10.1073/pnas.91.14.6458

    Article  PubMed  CAS  Google Scholar 

  27. Romero P, Gervois N, Schneider J et al (1997) Cytolytic T lymphocyte recognition of the immunodominant HLA-A*0201-restricted Melan-A/MART-1 antigenic peptide in melanoma. J Immunol 159:2366–2374

    PubMed  CAS  Google Scholar 

  28. Zippelius A, Bioley G, Le Gal FA et al (2004) Human thymus exports naive CD8 T cells that can home to nonlymphoid tissues. J Immunol 172:2773–2777

    PubMed  CAS  Google Scholar 

  29. Lima M, Almeida J, Santos AH et al (2001) Immunophenotypic analysis of the TCR-Vbeta repertoire in 98 persistent expansions of CD3(+)/TCR-alphabeta(+) large granular lymphocytes: utility in assessing clonality and insights into the pathogenesis of the disease. Am J Pathol 159:1861–1868

    PubMed  CAS  Google Scholar 

  30. Fass D, Kim PS (1995) Dissection of a retrovirus envelope protein reveals structural similarity to influenza hemagglutinin. Curr Biol 5:1377–1383. doi:10.1016/S0960-9822(95)00275-2

    Article  PubMed  CAS  Google Scholar 

  31. De Rossi A, Calabro ML, Panozzo M et al (1990) In vitro studies of HIV-1 infection in thymic lymphocytes: a putative role of the thymus in AIDS pathogenesis. AIDS Res Hum Retroviruses 6:287–298

    PubMed  Google Scholar 

  32. Vandekerckhove BA, Baccala R, Jones D et al (1992) Thymic selection of the human T cell receptor V beta repertoire in SCID-hu mice. J Exp Med 176:1619–1624. doi:10.1084/jem.176.6.1619

    Article  PubMed  CAS  Google Scholar 

  33. Donahue JP, Ricalton NS, Behrendt CE et al (1994) Genetic analysis of low V beta 3 expression in humans. J Exp Med 179:1701–1706. doi:10.1084/jem.179.5.1701

    Article  PubMed  CAS  Google Scholar 

  34. Tary-Lehmann M, Lehmann PV, Schols D et al (1994) Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras. J Exp Med 180:1817–1827. doi:10.1084/jem.180.5.1817

    Article  PubMed  CAS  Google Scholar 

  35. Ishikawa F, Yasukawa M, Lyons B et al (2005) Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood 106:1565–1573. doi:10.1182/blood-2005-02-0516

    Article  PubMed  CAS  Google Scholar 

  36. Lin C, Chen S, Yang L et al (2007) Evaluation of TCR Vbeta subfamily T cell expansion in NOD/SCID mice transplanted with human cord blood hematopoietic stem cells. Hematology 12:325–330. doi:10.1080/10245330701342342

    Article  PubMed  CAS  Google Scholar 

  37. Kerre TC, De Smet G, De Smedt M et al (2002) Adapted NOD/SCID model supports development of phenotypically and functionally mature T cells from human umbilical cord blood CD34(+) cells. Blood 99:1620–1626. doi:10.1182/blood.V99.5.1620

    Article  PubMed  CAS  Google Scholar 

  38. Pflumio F, Lapidot T, Murdoch B et al (1993) Engraftment of human lymphoid cells into newborn SCID mice leads to graft-versus-host disease. Int Immunol 5:1509–1522. doi:10.1093/intimm/5.12.1509

    Article  PubMed  CAS  Google Scholar 

  39. Hozumi N, Gorczynski R, Peters W et al (1994) A SCID mouse model for human immune response and disease. Res Immunol 145:370–379. doi:10.1016/S0923-2494(94)80202-5

    Article  PubMed  CAS  Google Scholar 

  40. Kirberg J, Bosco N, Deloulme JC et al (2008) Peripheral T lymphocytes recirculating back into the thymus can mediate thymocyte positive selection. J Immunol 181:1207–1214

    PubMed  CAS  Google Scholar 

  41. Dai S, Huseby ES, Rubtsova K et al (2008) Crossreactive T Cells spotlight the germline rules for alphabeta T cell-receptor interactions with MHC molecules. Immunity 28:324–334. doi:10.1016/j.immuni.2008.01.008

    Article  PubMed  CAS  Google Scholar 

  42. Jerne NK (1971) The somatic generation of immune recognition. Eur J Immunol 1:1–9. doi:10.1002/eji.1830010102

    Article  PubMed  CAS  Google Scholar 

  43. Van Laethem F, Sarafova SD, Park JH et al (2007) Deletion of CD4 and CD8 coreceptors permits generation of alphabetaT cells that recognize antigens independently of the MHC. Immunity 27:735–750

    Article  PubMed  CAS  Google Scholar 

  44. Moots RJ, Samberg NL, Pazmany L et al (1992) A cross-species functional interaction between the murine major histocompatibility complex class I alpha 3 domain and human CD8 revealed by peptide-specific cytotoxic T lymphocytes. Eur J Immunol 22:1643–1646. doi:10.1002/eji.1830220645

    Article  PubMed  CAS  Google Scholar 

  45. Barzaga-Gilbert E, Grass D, Lawrance SK et al (1992) Species specificity and augmentation of responses to class II major histocompatibility complex molecules in human CD4 transgenic mice. J Exp Med 175:1707–1715. doi:10.1084/jem.175.6.1707

    Article  PubMed  CAS  Google Scholar 

  46. Vignali DA, Moreno J, Schiller D et al (1992) Species-specific binding of CD4 to the beta 2 domain of major histocompatibility complex class II molecules. J Exp Med 175:925–932. doi:10.1084/jem.175.4.925

    Article  PubMed  CAS  Google Scholar 

  47. Zinkernagel RM, Althage A (1999) On the role of thymic epithelium vs. bone marrow-derived cells in repertoire selection of T cells. Proc Natl Acad Sci USA 96:8092–8097. doi:10.1073/pnas.96.14.8092

    Article  PubMed  CAS  Google Scholar 

  48. Park SH, Bae YM, Kim TJ et al (1992) HLA-DR expression in human fetal thymocytes. Hum Immunol 33:294–298. doi:10.1016/0198-8859(92)90338-N

    Article  PubMed  CAS  Google Scholar 

  49. Choi EY, Park WS, Jung KC et al (1997) Thymocytes positively select thymocytes in human system. Hum Immunol 54:15–20. doi:10.1016/S0198-8859(97)00012-8

    Article  PubMed  CAS  Google Scholar 

  50. Choi EY, Jung KC, Park HJ et al (2005) Thymocyte–thymocyte interaction for efficient positive selection and maturation of CD4 T cells. Immunity 23:387–396. doi:10.1016/j.immuni.2005.09.005

    Article  PubMed  CAS  Google Scholar 

  51. Li W, Sofi MH, Yeh N et al (2007) Thymic selection pathway regulates the effector function of CD4 T cells. J Exp Med 204:2145–2157

    PubMed  CAS  Google Scholar 

  52. Traggiai E, Chicha L, Mazzucchelli L et al (2004) Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304:104–107. doi:10.1126/science.1093933

    Article  PubMed  CAS  Google Scholar 

  53. Legrand N, Weijer K, Spits H (2006) Experimental models to study development and function of the human immune system in vivo. J Immunol 176:2053–2058

    PubMed  CAS  Google Scholar 

  54. Saito Y, Kametani Y, Hozumi K et al (2002) The in vivo development of human T cells from CD34(+) cells in the murine thymic environment. Int Immunol 14:1113–1124. doi:10.1093/intimm/dxf087

    Article  PubMed  CAS  Google Scholar 

  55. Radtke F, Wilson A, MacDonald HR (2004) Notch signaling in T- and B-cell development. Curr Opin Immunol 16:174–179. doi:10.1016/j.coi.2004.01.002

    Article  PubMed  CAS  Google Scholar 

  56. Radtke F, Wilson A, Mancini SJ et al (2004) Notch regulation of lymphocyte development and function. Nat Immunol 5:247–253. doi:10.1038/ni1045

    Article  PubMed  CAS  Google Scholar 

  57. de Pooter RF, Cho SK, Carlyle JR et al (2003) In vitro generation of T lymphocytes from embryonic stem cell-derived prehematopoietic progenitors. Blood 102:1649–1653. doi:10.1182/blood-2003-01-0224

    Article  PubMed  CAS  Google Scholar 

  58. Jaleco AC, Neves H, Hooijberg E et al (2001) Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J Exp Med 194:991–1002. doi:10.1084/jem.194.7.991

    Article  PubMed  CAS  Google Scholar 

  59. De Smedt M, Hoebeke I, Plum J (2004) Human bone marrow CD34+ progenitor cells mature to T cells on OP9-DL1 stromal cell line without thymus microenvironment. Blood Cells Mol Dis 33:227–232. doi:10.1016/j.bcmd.2004.08.007

    Article  PubMed  CAS  Google Scholar 

  60. Awong G, La Motte-Mohs RN, Zuniga-Pflucker JC (2007) Generation of pro-T cells in vitro: potential for immune reconstitution. Semin Immunol 19:341–349. doi:10.1016/j.smim.2007.10.005

    Article  PubMed  CAS  Google Scholar 

  61. De Smedt M, Reynvoet K, Kerre T et al (2002) Active form of Notch imposes T cell fate in human progenitor cells. J Immunol 169:3021–3029

    PubMed  Google Scholar 

  62. De Smedt M, Hoebeke I, Reynvoet K et al (2005) Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment. Blood 106:3498–3506. doi:10.1182/blood-2005-02-0496

    Article  PubMed  CAS  Google Scholar 

  63. Ciofani M, Zuniga-Pflucker JC (2007) The thymus as an inductive site for T lymphopoiesis. Annu Rev Cell Dev Biol 23:463–493. doi:10.1146/annurev.cellbio.23.090506.123547

    Article  PubMed  CAS  Google Scholar 

  64. Zhao Y, Parkhurst MR, Zheng Z et al (2007) Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res 67:2425–2429. doi:10.1158/0008-5472.CAN-06-3977

    Article  PubMed  CAS  Google Scholar 

  65. van Lent AU, Nagasawa M, van Loenen MM et al (2007) Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors. J Immunol 179:4959–4968

    PubMed  Google Scholar 

  66. Besseyrias V, Fiorini E, Strobl LJ et al (2007) Hierarchy of Notch–Delta interactions promoting T cell lineage commitment and maturation. J Exp Med 204:331–343. doi:10.1084/jem.20061442

    Article  PubMed  Google Scholar 

  67. Offner F, Van Beneden K, Debacker V et al (1997) Phenotypic and functional maturation of TCR gammadelta cells in the human thymus. J Immunol 158:4634–4641

    PubMed  CAS  Google Scholar 

  68. Jensen KD, Su X, Shin S et al (2008) Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity 29:90–100. doi:10.1016/j.immuni.2008.04.022

    Article  PubMed  CAS  Google Scholar 

  69. Havran WL, Allison JP (1988) Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335:443–445. doi:10.1038/335443a0

    Article  PubMed  CAS  Google Scholar 

  70. Boyden LM, Lewis JM, Barbee SD et al (2008) Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells. Nat Genet 40:656–662. doi:10.1038/ng.108

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank the many authors whose work provided important insights into the topic discussed within this manuscript but who could not be cited due to space limitations. TT is a post-doctoral fellow and TK is a Senior Clinical Investigator of the Fund for Scientific Research Flanders (FWO Vlaanderen). The work on this topic is supported by grants of the FWO and the Odysseus Research Program (TT) and the Interuniversity Attraction Poles Program (IUAP), supported by the Belgian Science Policy and the Concerted Research Action of Ghent University (GOA), supported by the Ghent University. We are indebted to Christiaan De Boever for performing art work.

Author information

Authors and Affiliations

  1. Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent University, De Pintelaan 185, 4 Blok A, 9000, Ghent, Belgium

    J. Plum, M. De Smedt, G. Leclercq, T. Taghon, T. Kerre & B. Vandekerckhove

Authors
  1. J. Plum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. De Smedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Leclercq
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Taghon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Kerre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B. Vandekerckhove
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Plum.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Plum, J., De Smedt, M., Leclercq, G. et al. Human intrathymic development: a selective approach. Semin Immunopathol 30, 411–423 (2008). https://doi.org/10.1007/s00281-008-0135-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-008-0135-2

Keywords

Search

Navigation