RAG1/2re-expression causes receptor revision in a model B cell line

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Abstract

The expression of RAG1 and RAG2 is essential for V(D)J rearrangement of the immunoglobulin (Ig) locus in developing B cells. In mature B cells further V(D)J rearrangement is suppressed and RAG1/2 proteins decline to undetectable levels. However, there is evidence that mature B cells in the periphery may re-express RAG1/2. In humans evidence of RAG1/2 re-expression is often linked with an autoimmune state, indicating that further understanding of re-expression may be crucial to understanding immune disorders. We have investigated the molecular consequences of RAG1/2 expression in mature lymphocytes using a cell culture system (M12 and DR3). M12 (IgG+, Igκ+ and RAG−) is a mouse B cell lymphoma. DR3 is a RAG1+/RAG2+ line derived from M12 by introduction of stable plasmids carrying RAG1 and RAG2 cDNAs. RAG1/2 mediated receptor revision occurs in the DR3 line, as evidenced by both the deletion of the endogenous rearranged Igκ gene segment (present in the parent M12 lines) and the presence of a new Igλ rearrangement. Gene expression profiles obtained through microarray analysis and RT-PCR found differences in expression levels between the two lines for: fibronectin, lysyl oxidase, TAP2, B220, Igκ, TIS11B, HMG2 and DNAPKcs. Thus, the expression of RAG1/2 in a previously RAG− cell line results in multiple changes to the gene expression profile as well as receptor revision. The significance of the changes found in this model of RAG re-expression is discussed.

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