Structural and functional evolution of the extracellular regions of T cell receptors

The primary structure of T cell receptor (TcR) heterodimers has been elucidated to varying degrees in 11 vertebrate species and the availability of these sequences provides a broader perspective for reassessing TcR evolution. Many features of the alpha beta TcR have been well conserved between divergent taxa whereas the structure and diversity of the gamma delta TcR is more variable. An alternative evolutionary scheme is presented whereby the gamma delta TcR and Ig molecules represent the earliest separation between specific cell mediated and humoral immunity with the alpha beta TcR emerging later. It is proposed that a set of ligands expressed on epithelia mediated the earliest selection of gamma delta T cells and B cells and was used as an antigen presentation substrate by gamma delta T cells. A subset of the earliest selection ligands became expert at binding small peptide fragments and the emergent 'classical' MHC molecules then co-evolved with the alpha beta TcR as obligate ligand-receptor pairs. Progression between the major stages in this sequence followed from adaptations in the selecting and presenting ligands and can be characterized as MHC 'capture'.