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 7

Overlap between TRB repertoires observed in blood or during evaluation for GVHD in the gastrointestinal tract and skin.

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Overlap between TRB repertoires observed in blood or during evaluation f...
TRB sequencing was retrospectively performed on biopsies obtained from 4 recipients on this study, identified by the codes along the top of the figure, who underwent evaluation of both GI tract and skin for suspected GVHD. The posttransplant days on which GI and skin biopsies were obtained from each recipient are superimposed on the abdomen and chest, respectively, of the cutaway torso representing each patient. Recipients 001-007, 002-001, and 002-010 were female, but a male torso is displayed for all recipients for the sake of simplicity. The approximate location from which each GI tract biopsy was obtained is indicated by the blue dots; the location from which the skin biopsies (green dots) were obtained is not indicated. The days below the red dot superimposed on the vein in the right arm of each torso indicate the posttransplant dates of collection of blood used for TRB sequencing of unfractionated and/or sorted cells. The Venn diagram below each torso indicates the total number of unique TRB sequences collectively found in the blood samples (PBMC, red), skin biopsies (green), or GI biopsies (blue) obtained from each recipient, as well as the number of TRB sequences that were shared between the 3 compartments.