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Thymopoiesis independent of common lymphoid progenitors

Nature Immunology volume 4, pages 168–174 (2003)Cite this article

Abstract

Early T lineage progenitors (ETPs) in the thymus are thought to develop from common lymphoid progenitors (CLPs) in the bone marrow (BM). We compared thymic ETPs to BM CLPs in mice and found that they differed in several respects. Thymic ETPs were not interleukin 7 (IL-7)–responsive and generated B lineage progeny with delayed kinetics, whereas BM CLPs were IL-7–responsive and rapidly generated B cells. ETPs sustained production of T lineage progeny for longer periods of time than BM CLPs. Analysis of Ikaros-deficient mice that exhibit ongoing thymopoiesis without B lymphopoeisis revealed near-normal frequencies of thymic ETPs, yet undetectable numbers of BM CLPs. We conclude that ETPs can develop via a CLP-independent pathway.

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Figure 1: Definition of the earliest thymic progenitors within the CD44+CD25− (DN1) compartment.
Figure 2: Cytokine responsiveness and surface phenotype of precursor populations.
Figure 3: B lineage production kinetics of defined precursor populations.
Figure 4: T lineage production kinetics of defined precursor populations.
Figure 5: Ikaros−/− mice contain ETPs but lack detectable BM CLPs.
Figure 6: D-J rearrangement status of IgH and TCRβ in precursor populations.

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References

  1. von Boehmer, H. & Fehling, H.J. Structure and function of the pre-T cell receptor. Annu. Rev. Immunol. 15, 433–452 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Wu, L., Antica, M., Johnson, G.R., Scollay, R. & Shortman, K. Developmental potential of the earliest precursor cells from the adult mouse thymus. J. Exp. Med. 174, 1617–1627 (1991).

    Article  CAS  Google Scholar 

  5. Matsuzaki, Y. et al. Characterization of c-Kit positive intrathymic stem cells that are restricted to lymphoid differentiation. J. Exp. Med. 178, 1283–1292 (1993).

    Article  CAS  Google Scholar 

  6. Kondo, M., Weissman, I.L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

    Article  CAS  Google Scholar 

  7. Izon, D. et al. A common pathway for dendritic cell and early B cell development. J. Immunol. 167, 1387–1392 (2001).

    Article  CAS  Google Scholar 

  8. Kondo, M. et al. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature 407, 383–386 (2000).

    Article  CAS  Google Scholar 

  9. Katsura, Y. Redefinition of lymphoid progenitors. Nat. Rev. Immunol. 2, 127–132 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Godfrey, D.I., Zlotnik, A. & Suda, T. Phenotypic and functional characterization of c-Kit expression during intrathymic T cell development. J. Immunol. 149, 2281–2285 (1992).

    CAS  PubMed  Google Scholar 

  12. Laky, K., Lefrancois, L., von Freeden-Jeffry, U., Murray, R. & Puddington, L. The role of IL-7 in thymic and extrathymic development of TCR γδ cells. J. Immunol. 161, 707–713 (1998).

    CAS  PubMed  Google Scholar 

  13. Wu, L. et al. CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus. Nature 349, 71–74 (1991).

    Article  CAS  Google Scholar 

  14. Miller, J.P. et al. The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. J. Exp. Med. 196, 705–711 (2002).

    Article  CAS  Google Scholar 

  15. Ikuta, K. & Weissman, I.L. Evidence that hematopoietic stem cells express mouse c-Kit but do not depend on steel factor for their generation. Proc. Natl. Acad. Sci. USA 89, 1502–1506 (1992).

    Article  CAS  Google Scholar 

  16. Adolfsson, J. et al. 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 (2001).

    Article  CAS  Google Scholar 

  17. Igarashi, H., Gregory, S., Yokota, T., Sakaguchi, N. & Kincade, P. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17, 117–130 (2002).

    Article  CAS  Google Scholar 

  18. Christensen, J.L. & Weissman, I.L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl. Acad. Sci. USA 98, 14541–14546 (2001).

    Article  CAS  Google Scholar 

  19. Rolink, A. et al. A subpopulation of B220+ cells in murine bone marrow does not express CD19 and contains natural killer cell progenitors. J. Exp. Med. 183, 187–194 (1996).

    Article  CAS  Google Scholar 

  20. Tudor, K.S., Payne, K.J., Yamashita, Y. & Kincade, P.W. Functional assessment of precursors from murine bone marrow suggests a sequence of early B lineage differentiation events. Immunity 12, 335–345 (2000).

    Article  CAS  Google Scholar 

  21. Li, Y.S., Wasserman, R., Hayakawa, K. & Hardy, R.R. Identification of the earliest B lineage stage in mouse bone marrow. Immunity 5, 527–535 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. King, A.G., Kondo, M., Scherer, D.C. & Weissman, I.L. Lineage infidelity in myeloid cells with TCR gene rearrangement: a latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling. Proc. Natl. Acad. Sci. USA 99, 4508–4513 (2002).

    Article  CAS  Google Scholar 

  24. Nichogiannopoulou, A., Trevisan, M., Neben, S., Friedrich, C. & Georgopoulos, K. Defects in hemopoietic stem cell activity in Ikaros mutant mice. J. Exp. Med. 190, 1201–1214 (1999).

    Article  CAS  Google Scholar 

  25. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I.L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

    Article  CAS  Google Scholar 

  26. Schlissel, M.S., Corcoran, L.M. & Baltimore, D. Virus-transformed pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription. J. Exp. Med. 173, 711–720 (1991).

    Article  CAS  Google Scholar 

  27. Medina, K.L. et al. Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen. Nat. Immunol. 2, 718–724 (2001).

    Article  CAS  Google Scholar 

  28. Kronenberg, M., Siu, G., Hood, L.E. & Shastri, N. The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu. Rev. Immunol. 4, 529–591 (1986).

    Article  CAS  Google Scholar 

  29. Godfrey, D.I., Kennedy, J., Suda, T. & Zlotnik, A. A developmental pathway involving four phenotypically and functionally distinct subsets of CD3−CD4−CD8− triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150, 4244–4252 (1993).

    CAS  Google Scholar 

  30. Winandy, S., Wu, L., Wang, J.H. & Georgopoulos, K. Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros. J. Exp. Med. 190, 1039–1048 (1999).

    Article  CAS  Google Scholar 

  31. Kurosawa, Y. et al. Identification of D segments of immunoglobulin heavy-chain genes and their rearrangement in T lymphocytes. Nature 290, 565–570 (1981).

    Article  CAS  Google Scholar 

  32. Born, W., White, J., Kappler, J. & Marrack, P. Rearrangement of IgH genes in normal thymocyte development. J. Immunol. 140, 3228–3232 (1988).

    CAS  PubMed  Google Scholar 

  33. Rodewald, H.R., Kretzschmar, K., Takeda, S., Hohl, C. & Dessing, M. Identification of pro-thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization. EMBO J. 13, 4229–4240 (1994).

    Article  CAS  Google Scholar 

  34. Soloff, R.S., Wang, T.G., Lybarger, L., Dempsey, D. & Chervenak, R. Transcription of the TCR-β locus initiates in adult murine bone marrow. J. Immunol. 154, 3888–3901 (1995).

    CAS  PubMed  Google Scholar 

  35. Gilbert, S.F. Developmental Biology (Sinauer Associates, Inc., Sunderland, MA, 2000).

    Google Scholar 

  36. Allman, D., Punt, J.A., Izon, D.J., Aster, J.C. & Pear, W.S. An invitation to T and more. Notch signaling in lymphopoiesis. Cell 109 (Suppl.) 1–11 (2002).

    Article  Google Scholar 

  37. Wang, J.H. et al. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5, 537–549 (1996).

    Article  CAS  Google Scholar 

  38. Sudo, T. et al. Expression and function of the interleukin 7 receptor in murine lymphocytes. Proc. Natl. Acad. Sci. USA 90, 9125–9129 (1993).

    Article  CAS  Google Scholar 

  39. McKearn, J.P., McCubrey, J. & Fagg, B. Enrichment of hematopoietic precursor cells and cloning of multipotential B-lymphocyte precursors. Proc. Natl. Acad. Sci. USA 82, 7414–7418 (1985).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Georgopoulos for Ikaros−/− mice and helpful discussions and W. Pear, M. Cancro and T. Laufer for reviewing this manuscript. We thank D. Fonseca for help with DNA sequencing and W. DeMuth, K. Rudd and R. C. Lindsley for expert technical assistance. We gratefully acknowledge the expert technical support in flow cytometry provided by the Abramson Cancer Center Flow Cytometry and Cell Sorting Shared Resource and in particular the efforts of R. Schretzenmair and H. Pletcher. Supported by NIH grants AI52861, AG20818 and AI053284 (to D.A.) and grant number IRG-78-002-25 from the American Cancer Society as well as grants from the Concern Foundation and the McCabe Fund (to A.B.).

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  1. Sungjune Kim

    Present address: Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104-6160, PA, USA

    David Allman, Arivazhagan Sambandam, Sungjune Kim, Juli P. Miller, David Well, Anita Meraz & Avinash Bhandoola

  2. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104-6160, PA, USA

    David Allman & Juli P. Miller

  3. Haverford College, Haverford, 19041, PA, USA

    Antonio Pagan

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Allman, D., Sambandam, A., Kim, S. et al. Thymopoiesis independent of common lymphoid progenitors. Nat Immunol 4, 168–174 (2003). https://doi.org/10.1038/ni878

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