Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide
Christopher G. Kanakry, David G. Coffey, Andrea M.H. Towlerton, Ante Vulic, Barry E. Storer, Jeffrey Chou, Cecilia C.S. Yeung, Christopher D. Gocke, Harlan S. Robins, Paul V. O’Donnell, Leo Luznik, Edus H. Warren
Christopher G. Kanakry, David G. Coffey, Andrea M.H. Towlerton, Ante Vulic, Barry E. Storer, Jeffrey Chou, Cecilia C.S. Yeung, Christopher D. Gocke, Harlan S. Robins, Paul V. O’Donnell, Leo Luznik, Edus H. Warren
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Research Article Immunology Oncology

Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide

Abstract

Posttransplantation cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD), but its immunologic impact is poorly understood. We assessed lymphocyte reconstitution via flow cytometry (n = 74) and antigen receptor sequencing (n = 35) in recipients of myeloablative, HLA-matched allogeneic BM transplantation using PTCy. Recovering T cells were primarily phenotypically effector memory with lower T cell receptor β (TRB) repertoire diversity than input donor repertoires. Recovering B cells were predominantly naive with immunoglobulin heavy chain locus (IGH) repertoire diversity similar to donors. Numerical T cell reconstitution and TRB diversity were strongly associated with recipient cytomegalovirus seropositivity. Global similarity between input donor and recipient posttransplant repertoires was uniformly low at 1–2 months after transplant but increased over the balance of the first posttransplant year. Blood TRB repertoires at ≥3 months after transplant were often dominated by clones present in the donor blood/marrow memory CD8+ compartment. Limited overlap was observed between the TRB repertoires of T cells infiltrating the skin or gastrointestinal tract versus the blood. Although public TRB sequences associated with herpesvirus- or alloantigen-specific CD8+ T cells were detected in some patients, posttransplant TRB and IGH repertoires were unique to each individual. These data define the immune dynamics occurring after PTCy and establish a benchmark against which immune recovery after other transplantation approaches can be compared.

Authors

Christopher G. Kanakry, David G. Coffey, Andrea M.H. Towlerton, Ante Vulic, Barry E. Storer, Jeffrey Chou, Cecilia C.S. Yeung, Christopher D. Gocke, Harlan S. Robins, Paul V. O’Donnell, Leo Luznik, Edus H. Warren

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Figure 8

Tracking T cell clones from donor blood, BM, and tissue to recipient blood and tissue.

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Tracking T cell clones from donor blood, BM, and tissue to recipient blo...
A CMV-seropositive patient (001-007) with AML received an allograft from her CMV-seronegative sister who had a history of inflammatory bowel disease. TRB sequencing was performed on donor blood and BM collected on the day of donation, and on tissue from gastrointestinal biopsies performed 8 months prior to donation that showed lymphocytic colitis. Three TRB sequences, denoted by the amino acid sequences encoded in their CDR3 regions, were shared between the BM, blood, and gastrointestinal biopsies from the donor and between the blood and gastrointestinal biopsies from the recipient. Although all 3 sequences were observed in the posttransplant blood and gastrointestinal tract biopsies of the recipient, who died of complications of gastrointestinal grade III acute GVHD, none were observed in a skin biopsy from the recipient, who also showed acute skin GVHD. Circles indicate the site of tissue sampling, and the color of the circle indicates the TRB sequence detected at that site.