Mechanisms of antigen receptor evolution

The adaptive immune system, which utilizes RAG-mediated recombination to diversify immune receptors, arose in ancestors of the jawed vertebrates approximately 500 million years ago. Homologs of immunoglobulins (Igs), T cell antigen receptors (TCRs), major histocompatibility complex (MHC) I and II, and the recombination activating genes (RAGs) have been identified in all extant classes of jawed vertebrates; however, no definitive ortholog of any of these genes has been identified in jawless vertebrates or invertebrates. Although the identity of the "primoridal" receptor that likely was interrupted by the recombination mechanism in the common ancestor of jawed vertebrates may never be established, many different families of genes that exhibit predicted characteristics of such a receptor have been described both within and outside the jawed vertebrates. Various model systems point toward a range of immune receptor diversity, encompassing many different families of recognition molecules, including non-diversified and diversified Ig-type variable (V) regions, as well as diversified VJ domains, whose functions are integrated in an organism's response to pathogenic invasion. The transition from the primordial antigen receptor to the monomeric Ig-/TCR-like domain and subsequent antigen-specific heterodimer likely involved progressive refinement of unique intermolecular associations in parallel with the acquisition of combinatorial diversity and antigen-specific recognition through somatic modification of the V region. RAG-mediated recombination and associated junctional diversification of both Ig and TCR genes occurs in all jawed vertebrates. In the case of Igs, somatic variation is expanded further through class switching, gene conversion, and somatic hypermutation. Various approaches, including both genomic and protein functional analyses, currently are being applied in jawless vertebrates, protochordates and other invertebrate deuterostome model systems in order to examine both RAG-mediated and alternative forms of antigen receptor diversification. Such studies have uncovered previously unknown mechanisms of generating receptor diversity.