Abstract
•T cell receptor (TCR) gene segment representation in the T cell repertoire is not random but instead has a symmetry corresponding to the location of the gene segments along the TCR locus.•The organization of the T cell repertoire demonstrates a mathematically definable clonal hierarchy that is evident at the total T cell level, as well as within CD4+ and CD8+ T cell subsets.•Following bone marrow transplantation, the T cell repertoire demonstrates diminished T cell clonal depth and diversity, but maintains the symmetry of TCR segment use seen in health.•The T cell repertoire post-transplantation is highly dynamic, with clonal hierarchy in the recipients demonstrating significant departure from the donors in patients who develop graft-versus-host disease.
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High-throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire, which makes it difficult to correlate T cell reconstitution with clinical outcomes. The associations identified thus far are of a broadly statistical nature, precluding precise modeling of outcomes based on T cell repertoire development following bone marrow transplantation (BMT). Previous work has demonstrated an inherent, mathematically definable order observed in the T cells from a diverse group of donors, which is perturbed in recipients following BMT. In this study, T cell receptor (TCR)-β sequences from HLA-matched related donor and recipient pairs are analyzed to further develop this methodology. TCR-β sequencing from unsorted and sorted T cell subsets isolated from the peripheral blood samples of BMT donors and recipients show conservation and symmetry of VJ segment usage in the clonal frequencies, linked to the organization of the gene segments along the TCR locus. This TCR-β VJ segment translational symmetry is preserved post-transplantation and even in cases of acute graft-versus-host disease (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antigens. The complexity of the repertoire is significantly diminished after BMT, and the T cell clonal hierarchy is altered post-transplantation. Low-frequency donor clones tended to take on a higher rank in the recipients following BMT, especially in patients with aGVHD. Over time, the repertoire evolves to a more donor-like state in the recipients who did not develop GVHD as opposed to those who did. The results presented here support new methods of quantifying and characterizing post-transplantation T cell repertoire reconstitution.
