Deep sequencing of the human TCRgamma and TCRbeta repertoires suggests that TCRbeta rearranges after alphabeta and gammadelta T cell commitment.

摘要

T lymphocytes respond to a broad array of pathogens with the combinatorial diversity of the T cell receptor (TCR). This adaptive response is possible because of the unique structure of the TCR, which is composed of two chains, either alphabeta or gammadelta, that undergo genetic rearrangement in the thymus. alphabeta and gammadelta T cells are functionally distinct within the host but are derived from a common multipotent precursor. The canonical model for T cell lineage commitment assumes that the gamma, delta, and beta chains rearrange before alphabeta or gammadelta T cell commitment. To test the standard model in humans, we used high-throughput sequencing to catalog millions of TCRgamma and TCRbeta chains from peripheral blood alphabeta and gammadelta T cells from three unrelated individuals. Almost all sampled alphabeta and gammadelta T cells had rearranged TCRgamma sequences. Although sampled alphabeta T cells had a diverse repertoire of rearranged TCRbeta chains, less than 4% of gammadelta T cells in peripheral blood had a rearranged TCRbeta chain. Our data suggest that TCRgamma rearranges in all T lymphocytes, consistent with TCRgamma rearranging before T cell lineage commitment. However, rearrangement of the TCRbeta locus appears to be restricted after T cell precursors commit to the alphabeta T cell lineage. Indeed, in T cell leukemias and lymphomas, TCRgamma is almost always rearranged and TCRbeta is only rearranged in a subset of cancers. Because high-throughput sequencing of TCRs is translated into the clinic for monitoring minimal residual for leukemia/lymphoma, our data suggest the sequencing target should be TCRgamma.