Evolution of the V, D, and J gene segments used in the primate γδ T-cell receptor reveals a dichotomy of conservation and diversity

gamma delta T cells are an immunological enigma in that both their function in the immune response and the molecular mechanisms behind their activation remain unclear. These cells predominate in the epithelia and can be rapidly activated to provide an array of responses. However, no homologous gamma delta T-cell populations have been identified between humans and mice, and our understanding of what these cells recognize as ligands is limited. Here we take an alternative approach to understanding human gamma delta T-cell ligand recognition by studying the evolutionary forces that have shaped the V, D, and J gene segments that are used during somatic rearrangement to generate the gamma delta T-cell receptor. We find that distinctly different forces have shaped the gamma and delta loci. The V delta and J delta genes are highly conserved, some even through to mouse. In contrast, the gamma-locus is split: the V gamma 9, V gamma 10, and V gamma 11 genes represent the conserved region of the V gamma gene locus whereas the remaining V gamma genes have been evolving rapidly, such that orthology throughout the primate lineage is unclear. We have also analyzed the coding versus silent substitutions between species within the V and J gene segments and find a preference for coding substitutions in the complementarity determining region loops of many of the V gene segments. Our results provide a different perspective on investigating human gamma delta T-cell recognition, demonstrating that diversification at particular gamma delta gene loci has been favored during primate evolution, suggesting adaptation of particular V domains to a changing ligand environment.