T Cell Repertoire Evolution After Allogeneic Bone Marrow Transplantation: An Organizational Perspective

Abstract

High throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire. In an attempt to correlate T cell reconstitution with clinical outcomes several measures of T cell repertoire complexity have emerged. However, the associations identified are of a broadly statistical nature, not allowing precise modeling of outcomes based on T cell repertoire development in clinical contexts such as following bone marrow transplantation (BMT). Previous work demonstrated that there is an inherent, mathematically definable order observed in the T cell population that is conserved in a diverse group of donors, and which is perturbed in recipients following BMT. Herein, we use a public database of human leukocyte antigen matched related-donor and recipient T cell receptor (TCR) {beta} sequences to further develop this methodology. TCR {beta} sequencing from unsorted T cells and sorted T cell subsets isolated from peripheral blood samples from BMT donors and recipients show remarkable 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 {beta} VJ segment translational symmetry is preserved post-transplant, and even in cases of acute GVHD (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antiges. We also observe that the complexity of the repertoire is significantly diminished after BMT and is not restored even years out post-transplant. The results here provide a new method of quantifying and characterizing post-transplant T cell repertoire reconstitution by further analyzing the mathematical rules governing TCR usage in the context of BMT. This approach may allow for a new means to correlate clinical outcomes with the evolving T cell repertoire post-transplant.