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Binding of LBP‐1a to specific immunoglobulin switch regions in vivo correlates with specific repression of class switch recombination
Author(s) -
Repetny Karen J.,
Zhong Xuemei,
Holodick Nichol E.,
Rothstein Thomas L.,
Hansen Ulla
Publication year - 2009
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200838226
Subject(s) - immunoglobulin class switching , isotype , biology , antibody , haematopoiesis , psychological repression , recombination , microbiology and biotechnology , b cell , immunoglobulin heavy chain , stimulation , immunoglobulin light chain , immunology , gene , genetics , gene expression , monoclonal antibody , stem cell , endocrinology
Abstract Upon stimulation of mature B cells, class switch recombination (CSR) can alter the specific immunoglobulin heavy chain constant region that is expressed. In a tissue culture cell line, we previously demonstrated that inhibition of late SV40 factor (LSF) family members enhanced IgM to IgA CSR. Here, isotype specificity of CSR regulation by LSF family members is addressed in primary mouse splenic B cells. First, we demonstrate that leader‐binding protein‐1a (LBP‐1a) is the prevalent family member in B lymphocytes. Second, we demonstrate by ChIP that LBP‐1a binds genomic sequences around mouse switch (S) regions in an isotype‐specific manner, in accordance with computational predictions: binding is observed to Sμ and Sα, but not to the tested Sγ1, regions. Importantly, binding of LBP‐1a is tightly regulated, with occupancy at genomic S regions dramatically decreasing following LPS stimulation. Finally, the consequence of DNA‐binding by LBP‐1a is determined using bone marrow chimeric mice in which LSF/LBP‐1 activity is inhibited in hematopoietic lineages. Upon in vitro stimulation of such primary B cells, CSR occurs with a higher efficiency to IgA, but not to IgG1. These results are supportive of a model whereby LBP‐1a represses CSR in an isotype‐specific manner via direct interaction with S regions involved in the recombination.