T cell antigen receptors in marsupials: A mix of ancient conservation and novel surprises

Two types of antigen receptors, B cell receptors or immunoglobulins (Ig) and T cell receptors (TCR), play a central role in the adaptive immune response of jawed vertebrates. TCR and Ig variable domains are capable of binding a vast array of antigens because they are generated by nearly random recombination of variable (V), diversity (D) and joining (J) gene segments. Marsupials are evolutionarily the closest relative to placental mammals. Their phylogenetic position makes them good models for comparative studies of their immune response relative to placental mammals. Compared to placentals, marsupials are born at a very immature stage which makes them useful models to study human fetal development. The goal of this study was to perform in-depth analyses of TCR in marsupials. The genomic organization and complexity of the four conventional TCR chains (alpha, beta, gamma and delta) in the grey short-tailed opossum Monodelphis domestica was found to be very similar to that of placental mammals. The regions encoding the four conventional TCR chains in the opossum have highly conserved synteny among marsupials and placental mammals and birds. Such conserved synteny across these distantly related species demonstrates a high level of stability in the TCR loci.;Nevertheless, an interesting surprise was discovered. Marsupials have an additional TCR not found in placental mammals. This TCR was named TCRmu for having been found first in marsupials. TCRmu occupies a distinct locus from those encoding the conventional TCR in the opossum. TCRmu has unique characteristics not found in the conventional TCR. TCRmu is the first TCR shown to contain pre-joined V genes in the germline DNA. Additionally, TCRmu is expressed as two different isoforms. The first isoform (TCRmicro1.0) encodes a two domain receptor much like conventional TCR. The second isoform (TCRmicro2.0) encodes a three domain receptor, similar to a novel TCR recently found in sharks. TCRmu was not found in placental mammals in spite of an exhaustive search of their available genomes. On the other hand, a clear TCRmu ortholog was found in the monotremes, suggesting that TCRmu may be present in other jawed vertebrates.