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, 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)-b sequences from HLA-matched related donor and recipient pairs are analyzed to further develop this methodology. TCR-b 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-b 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.

CDR3 and V- genes show distinct reconstitution patterns in T-cell repertoire post allogeneic bone marrow transplantation

“…We suggest that the shift of V-genes from patient to donor profile one year post transplant reflects the thymic de novo production of naïve T cells from donor origin in the six to twelfth months post transplantation. This has also been suggested by Meier et al(2019) (26).…”

“…As has been previously shown (26), the final long-term repertoire was more similar to that of the patient's original one than the donor's. We suggest a graphic illustration of the repertoires' reconstitution that is based on the results of our analyses, as shown in Figure 2E: One-month post transplantation, some recipients' repertoires share similarities with the donors and some are more similar to their own pre-transplant repertoires.…”

“…Current analytical approaches for the comparative analysis of TCR repertoires are mainly based on statistical inference and include repertoire diversity, repertoire overlap, V-gene and J-gene segments usage similarity, and amino acid composition of the CDR3 (24,25). A recent quantitative work on the organization of post allo-BMT repertoire compared donor-recipient TCRβ V-J repertoires by self-similarity mathematical measures and found differences between recipients who had GVHD and those who did not (26).…”

Recipient-specific T-cell repertoire reconstitution in the gut following murine hematopoietic cell transplant

“…A major question in the field is whether novel technologies that provide high-level resolution of the adaptive immune system, such as T-cell receptor repertoire sequencing (TCR-Seq), might clarify how acute GVHD occurs and possibly one day be used to help guide clinical decision-making to prevent or treat acute GVHD. [5][6][7] A key part of this effort involves methods to measure and understand the reproducibility of T-cell reconstitution after HCT. [8][9][10] Studies involving TCR spectratyping or cloning of specific TCR CDR3 sequences repertoire have shown oligoclonal expansion of T cells in GVHD-affected tissues in mouse models and human studies.…”

A comparative study of autogenous, allograft and artificial bone substitutes on bone regeneration and immunotoxicity in rat femur defect model

“…There was no significant difference between the percentage of CD8 T cells in autologous bone, artificial bone and allogenic bone, indicating that CD8 T cells had not been involved in immune rejection. Therefore, it is reasonable to believe that the immunogenicity of 3 bone substitutes was moderate and acceptable as bone implanting materials [ 57 ]. However, at different stages in vivo , especially at the early stage of implantation, the immunological indexes such as IgG, IgM concentration and CD4 T cells population of allogenic bone significantly increased to the degrees that were significantly higher than that of autogenous/artificial bone.…”