Recombination-activating genes, transposition, and the lymphoid-specific combinatorial immune system: a common evolutionary connection.

Abstract

The hallmarks that distinguish the gnathostome (jawed vertebrates) adaptive immune system from the immune system of agnathans (jawless fish), which both diverged from a common ancestor over 500 million years ago (MYA), include the presence of somatically rearranging antigen receptors (immunoglobulins, Ig; T cell receptors, TCR; new antigen receptor, NAR) via recombination activating molecules (Ragl and 2) and specific antigen-presentation molecules (MHC class I and II: Du Pasquier and Flajnik 1999). The process of somatic V(D)J recombination of antigen receptor gene segments, mediated by the Rag gene products, is the most significant characteristic of adaptive immunity in the jawed vertebrates. During this process a complex of Rag1 and Rag2 proteins initiates recombination by introducing DNA double strand breaks (DSBs) at evolutionarily conserved recombination signal sequences (RSS). These RSS flank the Ig and TCR (and NAR) germline variable region (VDJ) segments which are found in all gnathostomes (Du Pasquier and Flajnik 1999; Schatz et al. 1992). Expression of the Rag proteins is regulated at both the transcriptional and post-transcriptional levels, and co-expression of Rag1 and Rag2 is limited to lymphoid committed cells. In order to guarantee that the V(D)J recombinase acts only within the B and T lymphocyte lineage, the reaction is tightly regulated at multiple stages, including expression of the Rag genes themselves as well as controlled access of the recombination machinery to its substrates within chromatin.