TY - JOUR
T1 - T Cell Repertoire Evolution after Allogeneic Bone Marrow Transplantation
T2 - An Organizational Perspective
AU - Meier, Jeremy A.
AU - Haque, Mahdee
AU - Fawaz, Mohamed
AU - Abdeen, Hamdi
AU - Coffey, David
AU - Towlerton, Andrea
AU - Abdeen, Ahmed
AU - Toor, Abdullah
AU - Warren, Edus
AU - Reed, Jason
AU - Kanakry, Christopher G.
AU - Keating, Armand
AU - Luznik, Leo
AU - Toor, Amir A.
N1 - Funding Information:
Financial disclosure: A.A.T. was supported by research funding from National Cancer Center Support Grant P30-CA016059., Conflict of interest statement: There are no conflicts of interest to report., Authorship statement: J.M., M.H., and A.A.T. developed the study concept; L.L. and C.K. designed the clinical trial; J.M., M.H., M.F., H.A., A.T., and A.A. collected data; D.C., A.T., and W.H. performed the sequencing; J.M., M.H., M.F., H.A., A.T., A.A., and A.A.T. performed analyses; and J.M., M.H., M.F., H.A., A.T., A.A., D.C., A.T., W.H., L.L., C.K., A.K., J.R., and A.A.T. wrote the manuscript., Financial disclosure: See Acknowledgments on page 12.
Funding Information:
Financial disclosure: A.A.T. was supported by research funding from National Cancer Center Support Grant P30-CA016059.
Publisher Copyright:
© 2019 American Society for Blood and Marrow Transplantation
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Bone marrow transplantation
KW - Euclidean distance
KW - Graft-versus-host disease
KW - T cell receptor recombination
KW - T cell repertoire
KW - Translational symmetry
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UR - http://www.scopus.com/inward/citedby.url?scp=85061988801&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2019.01.021
DO - 10.1016/j.bbmt.2019.01.021
M3 - Article
C2 - 30677510
AN - SCOPUS:85061988801
VL - 25
SP - 868
EP - 882
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
SN - 1083-8791
IS - 5
ER -