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

Takashi Toya,Yoshiyuki Nakajima ,Kyoko Inamoto,Takeshi Kobayashi,Yuma Noguchi,Kazutaka Kitaura,Yuta Yamada,Junichi Mukae,Ryuji Suzuki,Hiroto Adachi,Tatsuya Konishi,Yuki Otsuka,Yuya Kishida,Aiko Igarashi,Akihito Nagata,Ayumi Taguchi,Yuho Najima,Kazuteru Ohashi,Ryosuke Konuma,Kota Yoshifuji,Atsushi Wada,Atsushi Marumo,Fumi Misumi,Kazuhiko Kakihana,Takeshi Nagamatsu

doi:10.1038/s41598-020-79363-2

Takashi Toya, Yoshiyuki Nakajima + Show 23 more

Open Access

https://doi.org/10.1038/s41598-020-79363-2

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Abstract

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.

Highlights

Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation
The diversity of T-cell receptor (TCR) repertoire of CMV-CTLs at the time of CMV reactivation was quite low in most patients, and this was represented by a low median Inverse Simpson’s index score of 1.595 (95% confidence interval 0.990–3.688) when compared to scores of previously published TCR diversity of bulk T-cells in peripheral blood (PB) of healthy individuals (729.7 ± 493.9, Fig. 1b)[37]
These results are consistent with a previous report by Link et al that evaluated the TCR repertoire of CMV-CTLs in four patients of type Human leukocyte antigen (HLA)-A*02:01 after allo-SCT23

Summary

Introduction

Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). 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. It has been reported that the diversity of HIV-specific TCR repertoire and the dominant clones in patients with HIV-1 can change dynamically during the clinical c ourse[26,27]. It has been proposed that early behavior of CMV-specific immunity after allo-SCT could be important for control of CMV v iremia[28], clonal dynamics of CMV-specific immunity, especially their short-term changes following CMV reactivation, remains to be elucidated

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