Evidence that productive rearrangements of TCR gamma genes influence the commitment of progenitor cells to differentiate into alpha beta or gamma delta T cells.

Abstract

Two models have been considered to account for the differentiation of gamma delta and alpha beta T cells from a common hematopoietic progenitor cell. In one model, progenitor cells commit to a lineage before T cell receptor (TCR) rearrangement occurs. In the other model, progenitor cells first undergo rearrangement of TCR gamma, delta, or both genes, and cells that succeed in generating a functional receptor commit to the gamma delta lineage, while those that do not proceed to attempt complete beta and subsequently alpha gene rearrangements. A prediction of the latter model is that TCR gamma rearrangements present in alpha beta T cells will be nonproductive. We tested this hypothesis by examining V gamma 2-J gamma 1C gamma 1 rearrangements, which are commonly found in alpha beta T cells. The results indicate that V gamma 2-J gamma 1C gamma 1 rearrangements in purified alpha beta T cell populations are almost all nonproductive. The low frequency of productive rearrangements of V gamma 2 in alpha beta T cells is apparently not due to a property of the rearrangement machinery, because a transgenic rearrangement substrate, in which the V gamma 2 gene harbored a frame-shift mutation that prevents expression at the protein level, was often rearranged in a productive configuration in alpha beta T cells. The results suggest that progenitor cells which undergo productive rearrangement of their endogenous V gamma 2 gene are selectively excluded from the alpha beta T cell lineage.