Mechanisms controlling expression of the RAG locus during lymphocyte development

Abstract

Recombination activating genes (RAG)1 and RAG2 are expressed in developing B and T lymphocytes and are required for the rearrangement of antigen receptor genes. In turn, RAG expression is regulated by the products of these assembled immunoglobulin (Ig) and T cell receptor (TCR) genes. Upon successful assembly of Ig genes, the antigen receptor is expressed on the immature B cell surface and tested for autoreactivity leading to either maintenance or inactivation of RAG expression. Successful assembly of TCR genes is followed by surface TCR expression and testing for its ability to interact with self-MHC, which if appropriate leads to the inactivation of RAG expression. Recent studies in B and T lymphocytes demonstrate that the reduction in RAG expression at the immature B and double-positive (DP) T cell stages is mediated through tonic (foreign antigen independent) receptor signaling. In B cells, tonic signaling activates PI(3)K and Akt kinases, which phosphorylate and lead to the cytoplasmic sequestration of FoxO proteins, the key transcriptional activators of RAG expression. In T cells, tonic signaling activates Abl and Erk kinases, leading to the transcriptional inactivation of RAGs.

Figure 1. Rag and NWC locus

Approximate locations of exons encodng UTRs (yellow and orange boxes) and coding regions (blue and red boxes) of Rag1/Rag2 and the first two exons of NWC. Below the locus are patterns of spliced transcripts for RAG1, RAG2, RAG1/NWC hybrid, and NWC.

Figure 2. Cis-regulatory elements in the RAG locus

A schematic diagram of the RAG locus and cis-regulatory elements in B and T cells. Yellow boxes indicate UTR and blue boxes indicate coding regions. Boxes upstream of the RAG2 promoter are regulatory elements. Below the locus is a chart of transcription factors known to bind the RAG locus and their binding sites.