Up-regulation of recombination activating gene expression by signal transduction through the surface Ig receptor.

Abstract

Recent evidence has demonstrated that a signal transduced through the lymphocyte Ag receptor may regulate the expression of the recombination activating genes (RAG). Although several groups have shown that such a signal may be required to down-regulate RAG-1 and RAG-2 after a functional Ag receptor has been generated in early mature T or B cells, recently it has been suggested that under some circumstances, cross-linking the B cell Ag receptor may result in up-regulation of RAG expression. To study this possibility, we used a unique set of cell variants isolated from a human mature B cell line, which differ in their expression of both the surface Ig receptor (sIg) and RAG-1 and RAG-2 genes. Two forms of stimulation were employed to generate a signal; either a soluble F(ab')2 anti-mu fragment or the combination of PMA and ionomycin. Northern blot analysis demonstrated that RAG-1 mRNA levels were increased in sIg+ variants after cross-linking with anti-mu. Increases were also observed in all variants after stimulation with PMA and ionomycin. Further analysis of cross-linked sIg+ variants suggests that the observed up-regulation in RAG expression was a reversible event. Furthermore, we have determined that both increased transcription and transcript stabilization contributed to this inducible up-regulation. We thus describe a mature B cell line in which RAG expression is up-regulated after sIg cross-linking. This finding is discussed in the context of its potential role in situations where sIg+ B cells may undergo secondary rearrangements for the purpose of "editing" their sIg receptors.