Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice.

Author information

Affiliations

  • 1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
      Authors
    • Siegel RM 1
    (1 author)

Proceedings of the National Academy of Sciences of the United States of America, 01 Aug 1992, 89(15):7003-7007
https://doi.org/10.1073/pnas.89.15.7003 PMID: 1495993 PMCID: PMC49633

Free full text in Europe PMC

Abstract 

The bcl-2 gene, which is overexpressed in human follicular B-cell lymphomas, has been found to extend cellular lifespan through inhibition of apoptosis, or programmed cell death. However, the physiological role of the Bcl-2 protein in lymphocyte development is unclear. We have established a transgenic mouse line that expresses high levels of the Bcl-2 protein in both cortical and medullary thymocytes, disrupting the normal pattern of expression of this gene. We found that in these mice, immature thymocytes became resistant to apoptosis mediated by corticosteroids and calcium ionophores. Untreated thymocytes also exhibited a survival advantage in suspension cultures compared with controls. In addition, overexpression of bcl-2 enabled a proportion of thymocytes and peripheral T cells to escape the process of clonal deletion, which normally eliminates self-reactive T cells during thymocyte maturation. These findings implicate the Bcl-2 protein in regulating the lifespan of maturing thymocytes and in the antigenic-selection process.

Free full text 

Logo of pnasLink to Publisher's site
Proc Natl Acad Sci U S A. 1992 Aug 1; 89(15): 7003–7007.
PMCID: PMC49633
PMID: 1495993

Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice.

R M Siegel, M Katsumata, T Miyashita, D C Louie, M I Greene, and J C Reed
Author information Copyright and License information Disclaimer

Abstract

The bcl-2 gene, which is overexpressed in human follicular B-cell lymphomas, has been found to extend cellular lifespan through inhibition of apoptosis, or programmed cell death. However, the physiological role of the Bcl-2 protein in lymphocyte development is unclear. We have established a transgenic mouse line that expresses high levels of the Bcl-2 protein in both cortical and medullary thymocytes, disrupting the normal pattern of expression of this gene. We found that in these mice, immature thymocytes became resistant to apoptosis mediated by corticosteroids and calcium ionophores. Untreated thymocytes also exhibited a survival advantage in suspension cultures compared with controls. In addition, overexpression of bcl-2 enabled a proportion of thymocytes and peripheral T cells to escape the process of clonal deletion, which normally eliminates self-reactive T cells during thymocyte maturation. These findings implicate the Bcl-2 protein in regulating the lifespan of maturing thymocytes and in the antigenic-selection process.

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 (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
 
icon of scanned page 7003
7003
icon of scanned page 7004
7004
icon of scanned page 7005
7005
icon of scanned page 7006
7006
icon of scanned page 7007
7007
 

Images in this article

Image
Image
on p.7004
Image
Image
on p.7005
Image
Image
on p.7006
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.
  • Tsujimoto Y, Croce CM. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5214–5218. [Europe PMC free article] [Abstract] [Google Scholar]
  • Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 1986 Oct 10;47(1):19–28. [Abstract] [Google Scholar]
  • Yunis JJ, Oken MM, Kaplan ME, Ensrud KM, Howe RR, Theologides A. Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin's lymphoma. N Engl J Med. 1982 Nov 11;307(20):1231–1236. [Abstract] [Google Scholar]
  • Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. [Abstract] [Google Scholar]
  • Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. [Abstract] [Google Scholar]
  • von Boehmer H, Kisielow P. Self-nonself discrimination by T cells. Science. 1990 Jun 15;248(4961):1369–1373. [Abstract] [Google Scholar]
  • Swat W, Ignatowicz L, von Boehmer H, Kisielow P. Clonal deletion of immature CD4+8+ thymocytes in suspension culture by extrathymic antigen-presenting cells. Nature. 1991 May 9;351(6322):150–153. [Abstract] [Google Scholar]
  • Huesmann M, Scott B, Kisielow P, von Boehmer H. Kinetics and efficacy of positive selection in the thymus of normal and T cell receptor transgenic mice. Cell. 1991 Aug 9;66(3):533–540. [Abstract] [Google Scholar]
  • Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer SJ. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961–6965. [Europe PMC free article] [Abstract] [Google Scholar]
  • Pezzella F, Tse AG, Cordell JL, Pulford KA, Gatter KC, Mason DY. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [Europe PMC free article] [Abstract] [Google Scholar]
  • Yui K, Komori S, Katsumata M, Siegel RM, Greene MI. Self-reactive T cells can escape clonal deletion in T-cell receptor V beta 8.1 transgenic mice. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7135–7139. [Europe PMC free article] [Abstract] [Google Scholar]
  • Louie DC, Kant JA, Brooks JJ, Reed JC. Absence of t(14;18) major and minor breakpoints and of Bcl-2 protein overproduction in Reed-Sternberg cells of Hodgkin's disease. Am J Pathol. 1991 Dec;139(6):1231–1237. [Europe PMC free article] [Abstract] [Google Scholar]
  • Reed JC, Meister L, Tanaka S, Cuddy M, Yum S, Geyer C, Pleasure D. Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin. Cancer Res. 1991 Dec 15;51(24):6529–6538. [Abstract] [Google Scholar]
  • Swat W, Ignatowicz L, Kisielow P. Detection of apoptosis of immature CD4+8+ thymocytes by flow cytometry. J Immunol Methods. 1991 Mar 1;137(1):79–87. [Abstract] [Google Scholar]
  • Sorenson CM, Barry MA, Eastman A. Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin. J Natl Cancer Inst. 1990 May 2;82(9):749–755. [Abstract] [Google Scholar]
  • McDonnell TJ, Nunez G, Platt FM, Hockenberry D, London L, McKearn JP, Korsmeyer SJ. Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population. Mol Cell Biol. 1990 May;10(5):1901–1907. [Europe PMC free article] [Abstract] [Google Scholar]
  • McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, Korsmeyer SJ. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989 Apr 7;57(1):79–88. [Abstract] [Google Scholar]
  • Grosschedl R, Weaver D, Baltimore D, Costantini F. Introduction of a mu immunoglobulin gene into the mouse germ line: specific expression in lymphoid cells and synthesis of functional antibody. Cell. 1984 Oct;38(3):647–658. [Abstract] [Google Scholar]
  • Storb U. Transgenic mice with immunoglobulin genes. Annu Rev Immunol. 1987;5:151–174. [Abstract] [Google Scholar]
  • Brombacher F, Lamers MC, Köhler G, Eibel H. Elimination of CD8+ thymocytes in transgenic mice expressing an anti-Lyt2.2 immunoglobulin heavy chain gene. EMBO J. 1989 Dec 1;8(12):3719–3726. [Europe PMC free article] [Abstract] [Google Scholar]
  • van Vliet E, Melis M, van Ewijk W. The influence of dexamethasone treatment on the lymphoid and stromal composition of the mouse thymus: a flowcytometric and immunohistological analysis. Cell Immunol. 1986 Dec;103(2):229–240. [Abstract] [Google Scholar]
  • Havran WL, Poenie M, Kimura J, Tsien R, Weiss A, Allison JP. Expression and function of the CD3-antigen receptor on murine CD4+8+ thymocytes. Nature. 1987 Nov 12;330(6144):170–173. [Abstract] [Google Scholar]
  • McConkey DJ, Nicotera P, Hartzell P, Bellomo G, Wyllie AH, Orrenius S. Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca2+ concentration. Arch Biochem Biophys. 1989 Feb 15;269(1):365–370. [Abstract] [Google Scholar]
  • Hengartner H, Odermatt B, Schneider R, Schreyer M, Wälle G, MacDonald HR, Zinkernagel RM. Deletion of self-reactive T cells before entry into the thymus medulla. Nature. 1988 Nov 24;336(6197):388–390. [Abstract] [Google Scholar]
  • MacDonald HR, Schneider R, Lees RK, Howe RC, Acha-Orbea H, Festenstein H, Zinkernagel RM, Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. [Abstract] [Google Scholar]
  • Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. [Abstract] [Google Scholar]
  • Kappler JW, Wade T, White J, Kushnir E, Blackman M, Bill J, Roehm N, Marrack P. A T cell receptor V beta segment that imparts reactivity to a class II major histocompatibility complex product. Cell. 1987 Apr 24;49(2):263–271. [Abstract] [Google Scholar]
  • Kappler JW, Staerz U, White J, Marrack PC. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. [Abstract] [Google Scholar]
  • Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. [Abstract] [Google Scholar]
  • Guidos CJ, Danska JS, Fathman CG, Weissman IL. T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages. J Exp Med. 1990 Sep 1;172(3):835–845. [Europe PMC free article] [Abstract] [Google Scholar]
  • Finkel TH, Cambier JC, Kubo RT, Born WK, Marrack P, Kappler JW. The thymus has two functionally distinct populations of immature alpha beta + T cells: one population is deleted by ligation of alpha beta TCR. Cell. 1989 Sep 22;58(6):1047–1054. [Abstract] [Google Scholar]
  • Shortman K, Vremec D, Egerton M. The kinetics of T cell antigen receptor expression by subgroups of CD4+8+ thymocytes: delineation of CD4+8+3(2+) thymocytes as post-selection intermediates leading to mature T cells. J Exp Med. 1991 Feb 1;173(2):323–332. [Europe PMC free article] [Abstract] [Google Scholar]
  • Strasser A, Harris AW, Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. [Abstract] [Google Scholar]
  • Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. [Abstract] [Google Scholar]
  • Wildin RS, Garvin AM, Pawar S, Lewis DB, Abraham KM, Forbush KA, Ziegler SF, Allen JM, Perlmutter RM. Developmental regulation of lck gene expression in T lymphocytes. J Exp Med. 1991 Feb 1;173(2):383–393. [Europe PMC free article] [Abstract] [Google Scholar]
  • Reynolds PJ, Lesley J, Trotter J, Schulte R, Hyman R, Sefton BM. Changes in the relative abundance of type I and type II lck mRNA transcripts suggest differential promoter usage during T-cell development. Mol Cell Biol. 1990 Aug;10(8):4266–4270. [Europe PMC free article] [Abstract] [Google Scholar]
  • Kramer MH, Raghoebier S, Beverstock GC, de Jong D, Kluin PM, Kluin-Nelemans JC. De novo acute B-cell leukemia with translocation t(14;18): an entity with a poor prognosis. Leukemia. 1991 Jun;5(6):473–478. [Abstract] [Google Scholar]
  • Yunis JJ, Mayer MG, Arnesen MA, Aeppli DP, Oken MM, Frizzera G. bcl-2 and other genomic alterations in the prognosis of large-cell lymphoma. N Engl J Med. 1989 Apr 20;320(16):1047–1054. [Abstract] [Google Scholar]
Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Full text links 

Read article at publisher's site: https://doi.org/10.1073/pnas.89.15.7003

Read article for free, from open access legal sources, via Unpaywall: https://europepmc.org/articles/pmc49633?pdf=renderUnpaywall

Citations & impact 

Impact metrics

85
Citations
Jump to Citations

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/41387140
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/41387140

Smart citations by scite.ai
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.1073/pnas.89.15.7003

Supporting
Mentioning
Contrasting
2
65
0

Article citations

Go to all (85) article citations

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Funding 

Funders who supported this work.

NCI NIH HHS (1)