Origins of the RAG Transposome and the MHC

Abstract

The appearance of adaptive immunity in vertebrates remains unclear, although many proposals have been made. In this speculative review, we describe the complex innate immune systems in place before the emergence of the vertebrates, and propose the existence of a molecule(s) on the surface of some cells able to present pathogen-associated molecular patterns (PAMPs) to a specific receptor(s) on other cells, much like molecules of the major histocompatibility complex (MHC) and T cell receptors (TCRs). Crucially, an MHC-like molecule with a mutation allowing it to recognize a new PAMP would be unlikely to be recognized by the specific TCR-like molecule, and so there would be no selection for the new MHC-like molecule whose gene would then be lost by neutral drift. The integration of the recombination activating gene (RAG) transposon in a TCR-like gene would have led to a significant increase in the recognition possibilities, so that new MHC-like variants could be recognized and selected, along with the new RAG/TCR-like system. The eventual consequence of this scenario would be the ability of the MHC to present many peptides, through multigene families, polymorphism of individual genes and an increase in peptide-binding repertoire (promiscuity).

Search for MHC/TCR-Like Systems in Living Organisms

“…We propose in the present article that this phenomenon could be universal. This figure has been reprinted with permission from Tsakou-Ngouafo et al (1). kin-recognition.…”

“…We define an MHC-like system as consisting of a polymorphic presenting molecule (the MHC) that recognizes a small molecule and interacts with a receptor capable of somatic diversification. The possibility that MHC-like could be polymorphic is based on our earlier proposition: the MHC polymorphism is due to the limited binding properties of the MHC binding pocket, compared to the capacity of recognition of the T cell receptor [( 1 ), see Figure 1A ].…”

“…The first kind of observation leads to the hypothesis that diversity, driven by somatic recombination, evolved many times during species evolution. Indeed the recombination activation gene (RAG), which is involved in the somatic TCR rearrangement, is a domesticated cut and paste transposon ( 1 , 2 ) belonging to the DDE transposon family. It has to be noted that the number of DDE transposons found in nature is huge ( 2 ) and that DDE transposons have been co-opted several times as site specific recombinase.…”

“…A DDE transposon (DNA cut and paste transpososon) named the RAG transposon, which is homolog to the RAG VDJ, has been described in non-vertebrate species (see for review 1). A likely hypothesis is that that the RAG DDE transposon invaded in the jawed vertebrate ancestor an IG-Like gene eventually resulting in the antibody/TCR rearrangement ( 1 , 44 ).…”

“…We first proposed this mechanism to explain the origin of the MHC polymorphism in the context of the origin of the adaptive system of jawed vertebrates [ Figure 1 and ( 1 )]. We proposed, before the origin of the jawed vertebrate adaptive immune system, that the pre-MHC system was able to recognize some Pathogen-associated molecular patterns (PAMPs) and present them to receptors able to recognize the pre-MHC plus the PAMPs.…”