• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Jul 23, 1996; 93(15): 7877–7881.

Deletion of the mouse T-cell receptor beta gene enhancer blocks alphabeta T-cell development.


Intrathymic T-cell development requires temporally regulated rearrangement and expression of T-cell receptor (TCR) genes. To assess the role of the TCR beta gene transcriptional enhancer (Ebeta) in this process, mouse strains in which Ebeta is deleted were generated using homologous recombination techniques. We report that mice homozygous for the Ebeta deletion, whether a selectable marker gene is present or not, show a block in alphabeta T-cell development at the CD4-CD8- double-negative cell stage, whereas the number of gammadelta+ T cells is normal, few CD4+CD8+ double-positive thymocytes and no alphabeta+ T cells are produced. DNA-PCR and RNA-PCR analyses of thymic cells from homozygous mutants showed no evidence of TCR beta gene rearrangement although germ-line Vbeta transcripts were detected at a low level, in heterozygous T cells, the targeted allele is not rearranged. Thus, deletion of Ebeta totally prevents rearrangement, but not transcription, of the targeted beta locus. These data formally establish the critical role played by Ebeta in cis-activation of the TCR beta locus for V(D)J recombination during alphabeta T-cell development.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Kisielow P, von Boehmer H. Development and selection of T cells: facts and puzzles. Adv Immunol. 1995;58:87–209. [PubMed]
  • Okada A, Alt FW. Mechanisms that control antigen receptor variable region gene assembly. Semin Immunol. 1994 Jun;6(3):185–196. [PubMed]
  • Godfrey DI, Zlotnik A. Control points in early T-cell development. Immunol Today. 1993 Nov;14(11):547–553. [PubMed]
  • Saint-Ruf C, Ungewiss K, Groettrup M, Bruno L, Fehling HJ, von Boehmer H. Analysis and expression of a cloned pre-T cell receptor gene. Science. 1994 Nov 18;266(5188):1208–1212. [PubMed]
  • Levelt CN, Eichmann K. Receptors and signals in early thymic selection. Immunity. 1995 Dec;3(6):667–672. [PubMed]
  • von Boehmer H. Positive selection of lymphocytes. Cell. 1994 Jan 28;76(2):219–228. [PubMed]
  • Capone M, Watrin F, Fernex C, Horvat B, Krippl B, Wu L, Scollay R, Ferrier P. TCR beta and TCR alpha gene enhancers confer tissue- and stage-specificity on V(D)J recombination events. EMBO J. 1993 Nov;12(11):4335–4346. [PMC free article] [PubMed]
  • Lauzurica P, Krangel MS. Temporal and lineage-specific control of T cell receptor alpha/delta gene rearrangement by T cell receptor alpha and delta enhancers. J Exp Med. 1994 Jun 1;179(6):1913–1921. [PMC free article] [PubMed]
  • Krimpenfort P, de Jong R, Uematsu Y, Dembic Z, Ryser S, von Boehmer H, Steinmetz M, Berns A. Transcription of T cell receptor beta-chain genes is controlled by a downstream regulatory element. EMBO J. 1988 Mar;7(3):745–750. [PMC free article] [PubMed]
  • Kühn R, Rajewsky K, Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. [PubMed]
  • Gu H, Zou YR, Rajewsky K. Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell. 1993 Jun 18;73(6):1155–1164. [PubMed]
  • Capone M, Curnow J, Bouvier G, Ferrier P, Horvat B. T cell development in TCR-alpha beta transgenic mice. Analysis using V(D)J recombination substrates. J Immunol. 1995 May 15;154(10):5165–5172. [PubMed]
  • Rouse RV, Bolin LM, Bender JR, Kyewski BA. Monoclonal antibodies reactive with subsets of mouse and human thymic epithelial cells. J Histochem Cytochem. 1988 Dec;36(12):1511–1517. [PubMed]
  • Anderson SJ, Abraham KM, Nakayama T, Singer A, Perlmutter RM. Inhibition of T-cell receptor beta-chain gene rearrangement by overexpression of the non-receptor protein tyrosine kinase p56lck. EMBO J. 1992 Dec;11(13):4877–4886. [PMC free article] [PubMed]
  • Levin SD, Anderson SJ, Forbush KA, Perlmutter RM. A dominant-negative transgene defines a role for p56lck in thymopoiesis. EMBO J. 1993 Apr;12(4):1671–1680. [PMC free article] [PubMed]
  • Mombaerts P, Clarke AR, Hooper ML, Tonegawa S. Creation of a large genomic deletion at the T-cell antigen receptor beta-subunit locus in mouse embryonic stem cells by gene targeting. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3084–3087. [PMC free article] [PubMed]
  • Mombaerts P, Clarke AR, Rudnicki MA, Iacomini J, Itohara S, Lafaille JJ, Wang L, Ichikawa Y, Jaenisch R, Hooper ML, et al. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature. 1992 Nov 19;360(6401):225–231. [PubMed]
  • Boehm T, Nehls M, Kyewski B. Transcription factors that control development of the thymic microenvironment. Immunol Today. 1995 Dec;16(12):555–556. [PubMed]
  • Qian L, Theodor L, Carter M, Vu MN, Sasaki AW, Wilkinson MF. T cell receptor-beta mRNA splicing: regulation of unusual splicing intermediates. Mol Cell Biol. 1993 Mar;13(3):1686–1696. [PMC free article] [PubMed]
  • Serwe M, Sablitzky F. V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron enhancer. EMBO J. 1993 Jun;12(6):2321–2327. [PMC free article] [PubMed]
  • Chen J, Young F, Bottaro A, Stewart V, Smith RK, Alt FW. Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus. EMBO J. 1993 Dec;12(12):4635–4645. [PMC free article] [PubMed]
  • Takeda S, Zou YR, Bluethmann H, Kitamura D, Muller U, Rajewsky K. Deletion of the immunoglobulin kappa chain intron enhancer abolishes kappa chain gene rearrangement in cis but not lambda chain gene rearrangement in trans. EMBO J. 1993 Jun;12(6):2329–2336. [PMC free article] [PubMed]
  • Fiering S, Epner E, Robinson K, Zhuang Y, Telling A, Hu M, Martin DI, Enver T, Ley TJ, Groudine M. Targeted deletion of 5'HS2 of the murine beta-globin LCR reveals that it is not essential for proper regulation of the beta-globin locus. Genes Dev. 1995 Sep 15;9(18):2203–2213. [PubMed]
  • Ferrier P, Krippl B, Blackwell TK, Furley AJ, Suh H, Winoto A, Cook WD, Hood L, Costantini F, Alt FW. Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate. EMBO J. 1990 Jan;9(1):117–125. [PMC free article] [PubMed]
  • Okada A, Mendelsohn M, Alt F. Differential activation of transcription versus recombination of transgenic T cell receptor beta variable region gene segments in B and T lineage cells. J Exp Med. 1994 Jul 1;180(1):261–272. [PMC free article] [PubMed]
  • Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. [PubMed]
  • Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. [PubMed]
  • Malissen M, Gillet A, Ardouin L, Bouvier G, Trucy J, Ferrier P, Vivier E, Malissen B. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO J. 1995 Oct 2;14(19):4641–4653. [PMC free article] [PubMed]
  • Fehling HJ, 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. [PubMed]
  • Tanaka Y, Ardouin L, Gillet A, Lin SY, Magnan A, Malissen B, Malissen M. Early T-cell development in CD3-deficient mice. Immunol Rev. 1995 Dec;148:171–199. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Gene
    Gene links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...