Class switching in B cells lacking 3' immunoglobulin heavy chain enhancers

John P. Manis, Nienke Van Der Stoep, Ming Tian, Roger Ferrini, Laurie Davidson, Andrea Bottaro, Frederick W. Alt

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128 Scopus citations

Abstract

The 40-kb region downstream of the most 3' immunoglobulin (Ig) heavy chain constant region gene (Cα) contains a series of transcriptional enhancers speculated to play a role in Ig heavy chain class switch recombination (CSR). To elucidate the function of this putative CSR regulatory region, we generated mice with germline mutations in which one or the other of the two most 5' enhancers in this cluster (respectively referred to as HS3a and HS1,2) were replaced either with a pgk-neo(r) cassette (referred to as HS3aN and HS1,2N mutations) or with a loxP sequence (referred to as HS3aΔ and HSI,2Δ, respectively). B cells homozygous for the HS3aN or HS1,2N mutations had severe defects in CSR to several isotypes. The phenotypic similarity of the two insertion mutations, both of which were cis- acting, suggested that inhibition might result from pgk-neo(r) cassette gene insertion rather than enhancer deletion. Accordingly, CSR returned to normal in B cells homozygous for the HS3aΔ or HS1,2Δ mutations. In addition, induced expression of the specifically targeted pgk-neo(r) genes was regulated similarly to that of germline C(H) genes. Our findings implicate a 3' CSR regulatory locus that appears remarkably similar in organization and function to the β-globin gene 5' LCR and which we propose may regulate differential CSR via a promoter competition mechanism.

Original languageEnglish (US)
Pages (from-to)1421-1431
Number of pages11
JournalJournal of Experimental Medicine
Volume188
Issue number8
DOIs
StatePublished - Oct 19 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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