Mechanisms controlling expression of the RAG locus during lymphocyte development.

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.