Surfing on the waves of the human γδ T cell ontogenic sea

While gamma delta T cells are present virtually in all vertebrates, there is a remarkable lack of conservation of the TRG and TRD loci underlying the generation of the gamma delta T cell receptor (TCR), which is associated with the generation of species-specific gamma delta T cells. A prominent example is the human phosphoantigen-reactive V gamma 9V delta 2 T cell subset that is absent in mice. Murine gamma delta thymocyte cells were among the first immune cells identified to follow a wave-based layered development during embryonic and early life, and since this initial observation, in-depth insight has been obtained in their thymic ontogeny. By contrast, less is known about the development of human gamma delta T cells, especially regarding the generation of gamma delta thymocyte waves. Here, after providing an overview of thymic gamma delta wave generation in several vertebrate classes, we review the evidence for gamma delta waves in the human fetal thymus, where single-cell technologies have allowed the breakdown of human gamma delta thymocytes into functional waves with important TCR associations. Finally, we discuss the possible mechanisms contributing to the generation of waves of gamma delta thymocytes and their possible significance in the periphery.