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. 1998 Sep 15;17(18):5349–5359. doi: 10.1093/emboj/17.18.5349

Evidence implicating Gfi-1 and Pim-1 in pre-T-cell differentiation steps associated with beta-selection.

T Schmidt 1, H Karsunky 1, B Rödel 1, B Zevnik 1, H P Elsässer 1, T Möröy 1
PMCID: PMC1170861  PMID: 9736613

Abstract

After rearrangement of the T-cell receptor (TCR) beta-locus, early CD4(-)/CD8(-) double negative (DN) thymic T-cells undergo a process termed 'beta-selection' that allows the preferential expansion of cells with a functional TCR beta-chain. This process leads to the formation of a rapidly cycling subset of DN cells that subsequently develop into CD4(+)/CD8(+) double positive (DP) cells. Using transgenic mice that constitutively express the zinc finger protein Gfi-1 and the serine/threonine kinase Pim-1, we found that the levels of both proteins are important for the correct development of DP cells from DN precursors at the stage where 'beta-selection' occurs. Analysis of the CD25(+)/CD44(-,lo) DN subpopulation from these animals revealed that Gfi-1 inhibits and Pim-1 promotes the development of larger beta-selected cycling cells ('L subset') from smaller resting cells ('E subset') within this subpopulation. We conclude from our data that both proteins, Pim-1 and Gfi-1, participate in the regulation of beta-selection-associated pre-T-cell differentiation in opposite directions and that the ratio of both proteins is important for pre-T-cells to pass the 'E' to 'L' transition correctly during beta-selection.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benoist C., Mathis D. Positive selection of T cells: fastidious or promiscuous? Curr Opin Immunol. 1997 Apr;9(2):245–249. doi: 10.1016/s0952-7915(97)80143-4. [DOI] [PubMed] [Google Scholar]
  2. Bouvier G., Watrin F., Naspetti M., Verthuy C., Naquet P., Ferrier P. Deletion of the mouse T-cell receptor beta gene enhancer blocks alphabeta T-cell development. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7877–7881. doi: 10.1073/pnas.93.15.7877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Crompton T., Gilmour K. C., Owen M. J. The MAP kinase pathway controls differentiation from double-negative to double-positive thymocyte. Cell. 1996 Jul 26;86(2):243–251. doi: 10.1016/s0092-8674(00)80096-3. [DOI] [PubMed] [Google Scholar]
  4. Dudley E. C., Petrie H. T., Shah L. M., Owen M. J., Hayday A. C. T cell receptor beta chain gene rearrangement and selection during thymocyte development in adult mice. Immunity. 1994 May;1(2):83–93. doi: 10.1016/1074-7613(94)90102-3. [DOI] [PubMed] [Google Scholar]
  5. Fehling H. J., Krotkova A., Saint-Ruf C., von Boehmer H. Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Nature. 1995 Jun 29;375(6534):795–798. doi: 10.1038/375795a0. [DOI] [PubMed] [Google Scholar]
  6. Fehling H. J., von Boehmer H. Early alpha beta T cell development in the thymus of normal and genetically altered mice. Curr Opin Immunol. 1997 Apr;9(2):263–275. doi: 10.1016/s0952-7915(97)80146-x. [DOI] [PubMed] [Google Scholar]
  7. Gilks C. B., Bear S. E., Grimes H. L., Tsichlis P. N. Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein. Mol Cell Biol. 1993 Mar;13(3):1759–1768. doi: 10.1128/mcb.13.3.1759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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. 1993 May 15;150(10):4244–4252. [PubMed] [Google Scholar]
  9. Godfrey D. I., Zlotnik A. Control points in early T-cell development. Immunol Today. 1993 Nov;14(11):547–553. doi: 10.1016/0167-5699(93)90186-O. [DOI] [PubMed] [Google Scholar]
  10. Graves J. D., Downward J., Izquierdo-Pastor M., Rayter S., Warne P. H., Cantrell D. A. The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes. J Immunol. 1992 Apr 15;148(8):2417–2422. [PubMed] [Google Scholar]
  11. Grimes H. L., Chan T. O., Zweidler-McKay P. A., Tong B., Tsichlis P. N. The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal. Mol Cell Biol. 1996 Nov;16(11):6263–6272. doi: 10.1128/mcb.16.11.6263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grimes H. L., Gilks C. B., Chan T. O., Porter S., Tsichlis P. N. The Gfi-1 protooncoprotein represses Bax expression and inhibits T-cell death. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14569–14573. doi: 10.1073/pnas.93.25.14569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Groettrup M., von Boehmer H. A role for a pre-T-cell receptor in T-cell development. Immunol Today. 1993 Dec;14(12):610–614. doi: 10.1016/0167-5699(93)90201-U. [DOI] [PubMed] [Google Scholar]
  14. Hoffman E. S., Passoni L., Crompton T., Leu T. M., Schatz D. G., Koff A., Owen M. J., Hayday A. C. Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo. Genes Dev. 1996 Apr 15;10(8):948–962. doi: 10.1101/gad.10.8.948. [DOI] [PubMed] [Google Scholar]
  15. Mallick C. A., Dudley E. C., Viney J. L., Owen M. J., Hayday A. C. Rearrangement and diversity of T cell receptor beta chain genes in thymocytes: a critical role for the beta chain in development. Cell. 1993 May 7;73(3):513–519. doi: 10.1016/0092-8674(93)90138-g. [DOI] [PubMed] [Google Scholar]
  16. Maraskovsky E., O'Reilly L. A., Teepe M., Corcoran L. M., Peschon J. J., Strasser A. Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/- mice. Cell. 1997 Jun 27;89(7):1011–1019. doi: 10.1016/s0092-8674(00)80289-5. [DOI] [PubMed] [Google Scholar]
  17. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  18. Murray R., Suda T., Wrighton N., Lee F., Zlotnik A. IL-7 is a growth and maintenance factor for mature and immature thymocyte subsets. Int Immunol. 1989;1(5):526–531. doi: 10.1093/intimm/1.5.526. [DOI] [PubMed] [Google Scholar]
  19. Möröy T., Grzeschiczek A., Petzold S., Hartmann K. U. Expression of a Pim-1 transgene accelerates lymphoproliferation and inhibits apoptosis in lpr/lpr mice. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10734–10738. doi: 10.1073/pnas.90.22.10734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pearse M., Wu L., Egerton M., Wilson A., Shortman K., Scollay R. A murine early thymocyte developmental sequence is marked by transient expression of the interleukin 2 receptor. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1614–1618. doi: 10.1073/pnas.86.5.1614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Peschon J. J., Morrissey P. J., Grabstein K. H., Ramsdell F. J., Maraskovsky E., Gliniak B. C., Park L. S., Ziegler S. F., Williams D. E., Ware C. B. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994 Nov 1;180(5):1955–1960. doi: 10.1084/jem.180.5.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Satoh T., Nakafuku M., Miyajima A., Kaziro Y. Involvement of ras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3314–3318. doi: 10.1073/pnas.88.8.3314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Scheijen B., Jonkers J., Acton D., Berns A. Characterization of pal-1, a common proviral insertion site in murine leukemia virus-induced lymphomas of c-myc and Pim-1 transgenic mice. J Virol. 1997 Jan;71(1):9–16. doi: 10.1128/jvi.71.1.9-16.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schmidt T., Zörnig M., Beneke R., Möröy T. MoMuLV proviral integrations identified by Sup-F selection in tumors from infected myc/pim bitransgenic mice correlate with activation of the gfi-1 gene. Nucleic Acids Res. 1996 Jul 1;24(13):2528–2534. doi: 10.1093/nar/24.13.2528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Selten G., Cuypers H. T., Berns A. Proviral activation of the putative oncogene Pim-1 in MuLV induced T-cell lymphomas. EMBO J. 1985 Jul;4(7):1793–1798. doi: 10.1002/j.1460-2075.1985.tb03852.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
  27. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  28. Swat W., Shinkai Y., Cheng H. L., Davidson L., Alt F. W. Activated Ras signals differentiation and expansion of CD4+8+ thymocytes. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4683–4687. doi: 10.1073/pnas.93.10.4683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Washburn T., Schweighoffer E., Gridley T., Chang D., Fowlkes B. J., Cado D., Robey E. Notch activity influences the alphabeta versus gammadelta T cell lineage decision. Cell. 1997 Mar 21;88(6):833–843. doi: 10.1016/s0092-8674(00)81929-7. [DOI] [PubMed] [Google Scholar]
  30. Willerford D. M., Swat W., Alt F. W. Developmental regulation of V(D)J recombination and lymphocyte differentiation. Curr Opin Genet Dev. 1996 Oct;6(5):603–609. doi: 10.1016/s0959-437x(96)80090-6. [DOI] [PubMed] [Google Scholar]
  31. Zweidler-Mckay P. A., Grimes H. L., Flubacher M. M., Tsichlis P. N. Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor. Mol Cell Biol. 1996 Aug;16(8):4024–4034. doi: 10.1128/mcb.16.8.4024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zörnig M., Schmidt T., Karsunky H., Grzeschiczek A., Möröy T. Zinc finger protein GFI-1 cooperates with myc and pim-1 in T-cell lymphomagenesis by reducing the requirements for IL-2. Oncogene. 1996 Apr 18;12(8):1789–1801. [PubMed] [Google Scholar]
  33. van Lohuizen M., Verbeek S., Krimpenfort P., Domen J., Saris C., Radaszkiewicz T., Berns A. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989 Feb 24;56(4):673–682. doi: 10.1016/0092-8674(89)90589-8. [DOI] [PubMed] [Google Scholar]
  34. von Freeden-Jeffry U., Solvason N., Howard M., Murray R. The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity. 1997 Jul;7(1):147–154. doi: 10.1016/s1074-7613(00)80517-8. [DOI] [PubMed] [Google Scholar]
  35. von Freeden-Jeffry U., Vieira P., Lucian L. A., McNeil T., Burdach S. E., Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med. 1995 Apr 1;181(4):1519–1526. doi: 10.1084/jem.181.4.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]

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