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Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):622-631
Stem Cell Transplantation
T-cell receptor-α repertoire of CD8+ T cells following allogeneic stem cell transplantation using next-generation sequencing
Cornelia S. Link-Rachner,1,2 Anne Eugster,2 Elke Rücker-Braun,1
Falk Heidenreich,1,3 Uta Oelschlägel,1 Andreas Dahl,2,4 Christian Klesse,3 Matthias Kuhn,5 Jan Moritz Middeke,1 Martin Bornhäuser,1,2 Ezio Bonifacio2 and Johannes Schetelig1,3
1Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, TU Dresden; 2DFG Research Center for Regenerative Therapies Dresden, TU Dresden; 3DKMS Clinical Trials Unit, Dresden; 4BIOTEChnology Center, TU Dresden and 5Institut für Medizinische Informatik und Biometrie (IMB), Medizinische Fakultät der TU Dresden, Germany
ABSTRACT
Alloreactivity or opportunistic infections following allogeneic stem cell transplantation are difficult to predict and contribute to post- transplantation mortality. How these immune reactions result in changes to the T-cell receptor repertoire remains largely unknown. Using next-generation sequencing, the T-cell receptor alpha (TRα) repertoire of naïve and memory CD8+ T cells from 25 patients who had received different forms of allogeneic transplantation was ana- lyzed. In parallel, reconstitution of the CD8+/CD4+ T-cell subsets was mapped using flow cytometry. When comparing the influence of anti-T- cell therapy, a delay in the reconstitution of the naïve CD8+ T-cell reper- toire was observed in patients who received in vivo T-cell depletion using antithymocyte globulin or post-transplantation cyclophosphamide in case of haploidentical transplantation. Sequencing of the TRα identified a repertoire consisting of more dominant clonotypes (>1% of reads) in these patients at 6 and 18 months post transplantation. When comparing donor and recipient, approximately 50% and approximately 80% of the donors' memory repertoire were later retrieved in the naïve and memory CD8+ T-cell receptor repertoire of the recipients, respectively. Although there was a remarkable expansion of single clones observed in the recip- ients' memory CD8+ TRα repertoire, no clear association between graft-versus-host disease or cytomegalovirus infection and T-cell receptor diversity was identified. A lower TRα diversity was observed in recipi- ents of a cytomegalovirus-seropositive donor (P=0.014). These findings suggest that CD8+ T-cell reconstitution in transplanted patients is influ- enced by the use of T-cell depletion or immunosuppression and the donor repertoire.
Introduction
Allogeneic stem cell transplantation (SCT) remains an essential component in the treatment of hematologic malignancies such as acute leukemia, lymphoma and myelodysplastic syndrome.1,2 Despite advances in transplantation regimens and sup- portive care, alloreactivity following SCT remains difficult to predict, and a large pro- portion of post-transplantation mortality is due to severe graft-versus-host reactions.3,4
T cells play an important role in the initiation of graft-versus-host disease (GvHD),5 in which the T-cell receptor (TCR) is a key element in the generation of an immune response against presented antigens. The heterodimeric TCR consists of an alpha (TRα) and beta (TRb) chain. Quantitative analyses of the TCR reper- toire by next-generation sequencing (NGS) allow a more sophisticated assessment of the adaptive immune system.6,7
The TCR repertoire has been proposed to modulate post-SCT outcomes. So far, TCR sequencing has largely been performed by sequencing the TRb in patients fol-
Correspondence:
CORNELIA S. LINK-RACHNER
cornelia.link@uniklinikum-dresden.de
Received: June 22, 2018.
Accepted: September 25, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.199802
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/622
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