umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Molecular genetics of B- and T-lymphocyte development
Umeå University, Faculty of Medicine, Medical Biosciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lymphocytes are essential for the generation of specific immunity. Development of B cells in the bone marrow and T cells in the thymus have several analogous features, and are tightly regulated processes. Even though there is an increasing amount of information concerning lymphopoiesis, a lot of questions remain. The aim of this thesis has been to understand some of the molecular events that contribute to the control of lymphocyte development.

Expression of the B cell receptor is an important checkpoint in B lymphocyte development. The Dµ protein is a truncated B cell receptor that can induce some of the signals elicited by full length µ, but cannot promote further B cell differentiation. In order to determine if this could stem from an impaired survival signal, we introduced Bcl-2 into RAG2 deficient Dµ transgenic mice. Analysis of these mice showed that Dµ could not support pre-B cell maturation despite extended survival of B cell precursors by Bcl-2. In addition, data from recombination competent Dµ transgenic mice demonstrated that the Dµ induced partial block is permissive for marginal zone B cell development, whereas the formation of follicular B cells is severely reduced.

The bHLH family of transcription factors is known to be involved in the regulation of lymphocyte development. Whereas the roles of E2A and HEB have been well documented in both B- and T-lymphocytes, detailed knowledge concerning E2-2 is lacking. To address the role of E2-2 in B cell development, we have reconstituted mice, using E2-2 deficient fetal liver cells, and analysed the B cell compartments. We also measured mRNA expression patterns for the three E-proteins in wildtype mice. Resulting data show that, in addition to a role in B cell lineage entry, E2-2 is required for efficient expansion of pro-B cells, and also influences the follicular versus marginal zone decision.

While focusing on assigning a role for E2-2 in T-cell development, we analyzed the expression of the E-proteins during this process and performed functional studies in fetal thymic organ cultures. E2-2 deficient mouse embryos were shown to display a partial block at the DN3 stage, which was not due to proliferation or apoptosis defects. In addition, analysis of expression levels of the pre-Talpha chain suggests that E2-2 may play a role in the regulation of transcription of pre-Talpha, and therefore in the assembly of the pre-T cell receptor.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2006. , 72 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1030
Keyword [en]
lymphocyte development, Dmu protein, transcription factor, bHLH, E2-2, T cell, B cell, marginal zone
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-802ISBN: 91-7264-089-8 (print)OAI: oai:DiVA.org:umu-802DiVA: diva2:144606
Public defence
2006-06-09, Betula, 6M, Norrlands Universitetssjukhus (NUS), Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-05-15 Created: 2006-05-15 Last updated: 2009-10-30Bibliographically approved
List of papers
1. Dmu expression causes enrichment of MZ B cells, but is non permissive for B cell maturation in Rag2-/- mice even if combined with Bcl-2.
Open this publication in new window or tab >>Dmu expression causes enrichment of MZ B cells, but is non permissive for B cell maturation in Rag2-/- mice even if combined with Bcl-2.
2006 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 43, no 9, 1316-1324 p.Article in journal (Refereed) Published
Abstract [en]

Rearrangements in reading frame 2 promote the expression of a truncated heavy chain, the Dmu protein. Dmu can assemble into a pre-B cell receptor like complex that appears to induce a subset of signals elicited by full length mu, but cannot promote the pro-B to pre-B cell transition of Rag-/- B cells. In order to determine if this could stem from an impaired survival signal not properly induced by the Dmu protein, we introduced Bcl-2 into Dmu-transgenic, Rag2-/- mice. Despite the fact that the Bcl-2 transgene expression promoted some increase in the fraction of CD43- B cells, an identical increase was also observed in Rag2-/- mice. Moreover, whereas in mu-transgenic Rag2-/-Bcl-2+ mice, CD2 and CD25 expression were up regulated and c-Kit was down regulated, these markers were unaltered in Dmu-transgenic Rag2-/- Bcl-2+ mice compared to Rag2-/- Bcl-2+ mice, indicating that Dmu cannot support pre-B cell maturation despite extended survival of B cell precursors by Bcl-2. In addition, we observed that in Dmu-transgenic recombination competent mice, the Dmu induced partial block is permissive for marginal zone B cell development whereas the formation of follicular B cells is severely reduced. While the Dmu protein is expressed in peripheral B cells escaping the block, only a minor fraction of Dmu is exposed to the outer cell surface.

Keyword
Animals, B-Lymphocytes/*cytology/*immunology, Base Sequence, Cell Differentiation, DNA/genetics, DNA-Binding Proteins/*deficiency/genetics, Gene Expression, Gene Rearrangement; B-Lymphocyte; Heavy Chain, Genes; bcl-2, Humans, Immunoglobulin mu-Chains/*genetics, Mice, Mice; Knockout, Mice; Transgenic
Identifiers
urn:nbn:se:umu:diva-15302 (URN)10.1016/j.molimm.2005.09.020 (DOI)16321440 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. E2-2 regulates the expansion of pro-B cells and follicular versus marginal zone decisions.
Open this publication in new window or tab >>E2-2 regulates the expansion of pro-B cells and follicular versus marginal zone decisions.
Show others...
2006 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 177, no 10, 6723-6729 p.Article in journal (Refereed) Published
Abstract [en]

The E-proteins E2A, HeLa E-box binding protein, and E2-2 constitute a class of basic helix-loop-helix transcription factors that differentially affect B cell development. E2A is by far the most investigated and appears to operate at several levels during B cell ontogeny. Less is known concerning the role of the other E-proteins. To address the role of E2-2, we have performed transfers of fetal liver (FL) cells into irradiated Rag-deficient mice. Although the transfer of E2-2-deficient cells alone can reconstitute all B cell subpopulations, albeit with a moderate reduction in cellularity, E2-2-deficient cells have a disadvantage when transferred together with wild-type cells. Cultivation of E2-2(-/-) day 14.5 FL cells on stromal cells and IL-7 revealed a reduced frequency of responding B cell progenitors despite normal IL-7Ralpha surface expression. Real-time PCR analysis revealed that E2-2 mRNA expression is high at the pro-B cell stage and drops sharply at the pre-B cell stage, consistent with a role for E2-2 in pro-B cells. In contrast, E2A mRNA was most abundant in pre-B cells. Analysis of the peripheral repertoire revealed that mice reconstituted with E2-2(-/-) FL cells had an increased proportion of marginal zone (MZ) B cells. Interestingly, E2-2 mRNA was elevated approximately 2-fold (p < 0.01) in follicular compared with MZ B cells. Although E2A mRNA showed a similar tendency, the difference was not significant. Collectively, our findings indicate that E2-2 is required for optimal expansion of pro-B cells, and also influences the follicular vs MZ decision.

Keyword
Animals, B-Lymphocyte Subsets/*cytology/immunology/metabolism/pathology, Cell Differentiation/genetics/*immunology, Cell Lineage/genetics/immunology, Cell Proliferation, Cells; Cultured, Interleukin-7/physiology, Liver/cytology/embryology/immunology, Mice, Mice; Inbred C57BL, Mice; Knockout, RNA; Messenger/biosynthesis, Spleen/*cytology/*immunology/pathology, Stem Cells/*cytology/immunology/metabolism/pathology, TCF Transcription Factors/biosynthesis/deficiency/*physiology
Identifiers
urn:nbn:se:umu:diva-15303 (URN)17082585 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
3. A non-redundant role for the bHLH transcription factor E2-2 in early thymocyte development
Open this publication in new window or tab >>A non-redundant role for the bHLH transcription factor E2-2 in early thymocyte development
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-5192 (URN)
Available from: 2006-05-15 Created: 2006-05-15 Last updated: 2012-08-10Bibliographically approved

Open Access in DiVA

fulltext(360 kB)1063 downloads
File information
File name FULLTEXT01.pdfFile size 360 kBChecksum SHA-1
447a07a41f84e53c28adaa4d86685094417cd8768bd158dc77df7d3aebdc37b7cde4783a
Type fulltextMimetype application/pdf

By organisation
Medical Biosciences
Medical Genetics

Search outside of DiVA

GoogleGoogle Scholar
Total: 1063 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 582 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf