Deep Sequencing of the Human TCRγ and TCRβ Repertoires Suggests that TCRβ Rearranges After αβ and γδ T Cell Commitment

Deep sequencing provides new insights about T cell receptor rearrangement in humans. Feng Shui for T Cells In the ancient art of feng shui, buildings and even furniture are rearranged to more auspicious orientations. Lymphocytes are the feng shui masters of the immune system. Unlike other cells, which distinguish themselves by differentially expressing certain genes, T lymphocytes and other cells of the adaptive immune system actively rearrange their DNA, cutting and splicing different parts of their antigen receptor genes to respond to the vast number of pathogens that can attack the body. It has been long thought that for T lymphocytes, functional T cell receptor (TCR) chain rearrangement was required for T cell commitment to a particular lineage and function. Sherwood et al. now use deep sequencing of the repertoires of two chains of the TCR, TCRγ and TCRβ, to show that TCRβ may rearrange after lineage commitment. The two main lineages of T cells are classified based on their TCR usage: αβ and γδ T cells. These cells have different functions and are found in different locations in the body: αβ T cells respond to peptides presented in the context of human leukocyte antigen (HLA) molecules and are the predominant T cells in the blood, whereas γδ T cells may not bind HLA-peptide complexes and are found frequently in the lining of the gut. It had previously been thought that TCRβ, γ, and δ chains all rearranged before a T cell’s commitment to one or the other lineage, which suggests a decisive role for rearrangement in the commitment choice. However, Sherwood et al. show through deep sequencing of millions of TCRs in either γδ or αβ T cells that although TCRγ is rearranged in all T lymphocytes, TCRβ is rearranged only in less than 4% of γδ T cells. These data suggest that TCRβ rearrangement may not be required for lineage commitment after all. Moreover, they see both common and diverse TCR rearrangements in γδ T cells, which indicate possible adaptive- and innate-like roles for these two populations. Thus, TCR rearrangement may not only increase TCR diversity but also guide function as well. After all, what could be more auspicious than a healthy immune system? 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 αβ or γδ, that undergo genetic rearrangement in the thymus. αβ and γδ 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 γ, δ, and β chains rearrange before αβ or γδ T cell commitment. To test the standard model in humans, we used high-throughput sequencing to catalog millions of TCRγ and TCRβ chains from peripheral blood αβ and γδ T cells from three unrelated individuals. Almost all sampled αβ and γδ T cells had rearranged TCRγ sequences. Although sampled αβ T cells had a diverse repertoire of rearranged TCRβ chains, less than 4% of γδ T cells in peripheral blood had a rearranged TCRβ chain. Our data suggest that TCRγ rearranges in all T lymphocytes, consistent with TCRγ rearranging before T cell lineage commitment. However, rearrangement of the TCRβ locus appears to be restricted after T cell precursors commit to the αβ T cell lineage. Indeed, in T cell leukemias and lymphomas, TCRγ is almost always rearranged and TCRβ 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 TCRγ.