Bruton's Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement

Bruton's tyrosine kinase (Btk) and the adapter protein SLP-65 (Src homology 2 domain-containing leukocyte-specific phosphoprotein of 65 kDa) transmit precursor BCR (pre-BCR) signals that are essential for efficient developmental progression of large cycling into small resting pre-B cells. We sh...

Full description

Saved in:
Bibliographic Details
Published in:Journal of Immunology 2006-04, Vol.176 (8), p.4543-4552
Main Authors: Kersseboom, Rogier, Ta, Van B. T, Zijlstra, A. J. Esther, Middendorp, Sabine, Jumaa, Hassan, Fokko van Loo, Pieter, Hendriks, Rudolf W
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Agammaglobulinaemia Tyrosine Kinase
Animals
B-Lymphocytes - cytology
B-Lymphocytes - drug effects
B-Lymphocytes - immunology
Base Sequence
Carrier Proteins - genetics
Carrier Proteins - immunology
Cell Differentiation
Cell Proliferation
Cell Survival
DNA, Complementary - genetics
Gene Rearrangement, B-Lymphocyte, Light Chain
Interleukin-7 - pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Phosphoproteins - deficiency
Phosphoproteins - genetics
Phosphoproteins - immunology
Protein-Tyrosine Kinases - deficiency
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - immunology
Signal Transduction - drug effects
Transcription, Genetic
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Bruton's tyrosine kinase (Btk) and the adapter protein SLP-65 (Src homology 2 domain-containing leukocyte-specific phosphoprotein of 65 kDa) transmit precursor BCR (pre-BCR) signals that are essential for efficient developmental progression of large cycling into small resting pre-B cells. We show that Btk- and SLP-65-deficient pre-B cells have a specific defect in Ig lambda L chain germline transcription. In Btk/SLP-65 double-deficient pre-B cells, both kappa and lambda germline transcripts are severely reduced. Although these observations point to an important role for Btk and SLP-65 in the initiation of L chain gene rearrangement, the possibility remained that these signaling molecules are only required for termination of pre-B cell proliferation or for pre-B cell survival, whereby differentiation and L chain rearrangement is subsequently initiated in a Btk/SLP-65-independent fashion. Because transgenic expression of the antiapoptotic protein Bcl-2 did not rescue the developmental arrest of Btk/SLP-65 double-deficient pre-B cells, we conclude that defective L chain opening in Btk/SLP-65-deficient small resting pre-B cells is not due to their reduced survival. Next, we analyzed transgenic mice expressing the constitutively active Btk mutant E41K. The expression of E41K-Btk in Ig H chain-negative pro-B cells induced 1) surface marker changes that signify cellular differentiation, including down-regulation of surrogate L chain and up-regulation of CD2, CD25, and MHC class II; and 2) premature rearrangement and expression of kappa and lambda light chains. These findings demonstrate that Btk and SLP-65 transmit signals that induce cellular maturation and Ig L chain rearrangement independently of their role in termination of pre-B cell expansion.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.176.8.4543