Genetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation

Bühler, Stéphane; Bettens, Florence; Dantin, Carole; Ferrari‐Lacraz, Sylvie; Ansari, Marc; Mamez, Anne‐Claire; Masouridi‐Levrat, Stavroula; Chalandon, Yves; Villard, Jean

doi:10.1038/s41375-019-0654-y

Cited by 24 publications

(35 citation statements)

References 64 publications

(64 reference statements)

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“…Indeed, the primary objective of this study was to evaluate whether a more direct measure of T cell clonal diversity (as measured by high-throughput sequencing) was correlated with clinical outcome, in particular an increased risk of mortality during the first year posttransplant in patients undergoing myeloablative CBT. Differently than our study, Buhler et al recently showed that TCR diversity was not predictive of GVHD, relapse, death, or infections post-HCT in a cohort of 116 donor/recipient pairs undergoing an allogeneic HCT (unrelated = 42; related = 70; haploidentical = 4) ( 25 ). However, the latter study analyzed TCR diversity shortly before transplantation (time point 1) and at 1-year post-HCT (time point 2).…”

Section: Discussioncontrasting

confidence: 97%

Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation

et al. 2020

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Introduction Cord blood transplantation (CBT) recipients are at increased risk of mortality due to delayed immune recovery (IR). Prior studies in CBT patients have shown that recovery of absolute lymphocyte count is predictive of survival after transplant. However, there are no data on the association of T-cell receptor (TCR) and clinical outcomes after CBT. Here we retrospectively performed TCR beta chain sequencing on peripheral blood (PB) samples of 34 CBT patients. Methods All patients received a total body irradiation based conditioning regimen and cyclosporine and MMF were used for graft versus host disease (GvHD) prophylaxis. PB was collected pretransplant on days 28, 56, 80, 180, and 1-year posttransplant for retrospective analysis of IR utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells. To test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived. Results Median age was 27 (range 1–58 years) and most of the patients (n = 27) had acute leukemias. There were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths were due to relapse. Rapid turnover of T cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01). Conclusions Using a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.

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Section: Discussioncontrasting

confidence: 97%

Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation

et al. 2020

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“…Donors and pre-transplant recipients' repertoires were the most distant. This is in accordance with the findings of Buhler et al,(2019) (40), who studied a large cohort of 116 full chimeric recipients and their respective HSC donors pre-transplant and at 1 year post-transplant. The recipients' repertoire one year post transplant was very different from the donors', with only a few overlaps.…”

Section: Discussionsupporting

confidence: 93%

“…The recipients' repertoire one year post transplant was very different from the donors', with only a few overlaps. This finding led them to suggest that a new repertoire can be reconstituted at any age through thymic dependent or independent pathways (40).…”

Section: Discussionmentioning

confidence: 99%

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

Tickotsky

Dvorkin

Rotkopf

et al. 2020

Preprint

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Restoration of T-cell repertoire diversity after allogenic bone marrow transplantation (allo-BMT) is crucial for immune recovery. T-cell diversity is produced by rearrangements of germline gene segments (V (D) and J) of the T-cell receptor (TCR) α and β chains. During segment joining, nucleotide inserted and deleted at the junctions between pairs of rearranging genes form the complementarity determining region 3 (CDR3).We used a new means of comparing multiple T-cell repertoires to follow T cell repertoire changes post allo-BMT in HLA-matched related donor and recipient pairs. Our analyses of the differences between donor and recipient CDR3 beta composition and V-gene profile show that a duality exists between the reconstitution of these two following transplantation; while CDR3 sequences were consistently influenced by recipients' parameters, V genes followed a time-dependent pattern, as they got the donor profile following transplant and then shifted back to the recipients' profile. The final 2 long term repertoire was more similar to that of the recipient's original one than the donor's; some recipients converged within months while others took multiple years.Based on the results of our analyses, we propose that donor-recipient V-gene distribution differences may serve as clinical biomarkers for monitoring immune recovery.

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“…In this study, a larger number of patients was analyzed and results indicated that shared TCRs were common within allo-SCT recipients with CMV reactivation. These data were consistent with data from the previous study which reported that repertoire overlap was significantly driven by CMV but otherwise remained markedly limited 39 . Although frequency of shared TCRs and the number that is shared can depend on cohort size and sampling depth 40 , the higher frequency of shared clonotypes and markedly similar CDR3 sequences observed suggested that they may play important roles.…”

Section: Discussionsupporting

confidence: 92%

T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation

Toya

Taguchi

Kitaura³

et al. 2020

Sci Rep

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Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8+/CMV pp65 tetramer+ cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson’s index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2–4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.

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Genetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation

Cited by 24 publications

References 64 publications

Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation

Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation

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

T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation

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