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CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation.
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MedLine Citation:
PMID:  8666928     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The CD45 transmembrane glycoprotein has been shown to be a protein phosphotyrosine phosphatase and to be important in signal transduction in T and B lymphocytes. We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45. The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls. The increase in B cell numbers is due to the specific expansion of two B cell subpopulations that express high levels of immunoglobulin (IgM) staining. T cell development is significantly inhibited in CD45-null animals at two distinct stages. The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both positive and negative selection require signals through the TCR complex, these findings suggest that CD45 is an important regulator of signal transduction via the TCR complex at multiple stages of T cell development. CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals. The proliferation of B cells in response to CD38 cross-linking is significantly reduced but not abolished by the CD45-null mutation. We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells.
Authors:
K F Byth; L A Conroy; S Howlett; A J Smith; J May; D R Alexander; N Holmes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of experimental medicine     Volume:  183     ISSN:  0022-1007     ISO Abbreviation:  J. Exp. Med.     Publication Date:  1996 Apr 
Date Detail:
Created Date:  1996-08-05     Completed Date:  1996-08-05     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985109R     Medline TA:  J Exp Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1707-18     Citation Subset:  IM    
Affiliation:
Department of Pathology, Cambridge University, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
ADP-ribosyl Cyclase
Animals
Antigens, CD*
Antigens, CD38
Antigens, CD40 / metabolism
Antigens, CD45 / genetics,  metabolism*
Antigens, Differentiation / metabolism
B-Lymphocytes / immunology
Hematopoietic Stem Cells / immunology*
Immunoglobulin D / biosynthesis
Immunoglobulin M / biosynthesis
Lymphocyte Activation
Lymphocytes / immunology*
Membrane Glycoproteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
N-Glycosyl Hydrolases / metabolism
Organ Culture Techniques
Receptors, Antigen / metabolism
Selection, Genetic
Signal Transduction*
Spleen / cytology,  immunology
T-Lymphocyte Subsets / immunology
Thymus Gland / cytology,  growth & development*
Grant Support
ID/Acronym/Agency:
//Wellcome Trust
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, CD40; 0/Antigens, Differentiation; 0/Immunoglobulin D; 0/Immunoglobulin M; 0/Membrane Glycoproteins; 0/Receptors, Antigen; EC 3.1.3.48/Antigens, CD45; EC 3.2.2.-/N-Glycosyl Hydrolases; EC 3.2.2.5/ADP-ribosyl Cyclase; EC 3.2.2.5/Antigens, CD38; EC 3.2.2.5/Cd38 protein, mouse
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Full Text
Journal Information
Journal ID (nlm-ta): J Exp Med
ISSN: 0022-1007
ISSN: 1540-9538
Publisher: The Rockefeller University Press
Article Information
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Print publication date: Day: 1 Month: 4 Year: 1996
Volume: 183 Issue: 4
First Page: 1707 Last Page: 1718
ID: 2192485
Publisher Id: 96261671
PubMed Id: 8666928

CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation


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