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Editorials
view of the interest in the depletion of naïve T cells from stem cell grafts in the related donor setting.14 However, further research will be needed to understand if this occurs also on the other HSCT platforms, including cord blood transplantation,15 and what the desired qualities of a donor repertoire are.
Figure 2. Relative contribution of donor memory or naïve CD8+ T cells to the patients’ repertoires at six months post hematopoietic stem cell transplanta- tion (HSCT). The average percentage of T-cell receptor-α clonotypes in memory (M; dark orange) or naïve (N; light orange) CD8+ T cells shared between 5 donors (left) and the respective patients at day 180 after HLA-identical sibling HSCT in the absence of T-cell-depleting immunosuppressive therapy. Shaded blue areas indicate shrinking or expansion of the relative percentage of shared clonotypes in the donor compared to the patient post transplantation. Non-shared clono- types are indicated in gray. Note that an average of approximately 60% and 11.5% of the patients’ memory and naïve repertoires, respectively, could be traced back to the donors’ memory repertoires. In contrast, an average of only approximately 30% and 15% of the patients’ memory and naïve repertoires, respectively, could be traced back to the donors’ naïve repertoires. This figure uses data from Figure 2A of the study by Link-Rachner et al.1
The study by Link-Rachner et al. does leave some open questions that warrant further study. First, patients who relapsed were explicitly excluded from the study. However, relapse remains the main cause of treatment fail- ure in HSCT,16 and, similar to GvHD, a central role for T cells in the therapeutic graft-versus-leukemia effect has been well established.17 Hence, NGS-based studies of T-cell repertoire characteristics that might associate with leukemia relapse after transplantation are of the foremost importance. Second, in this study, CD4+ T-cell reconstitu- tion and repertoire dynamics were not analyzed, yet they are likely to play a central role in patients after HSCT, espe- cially in clinical contexts where HLA-DPB1 mismatches are frequent (e.g. HSCT with unrelated donors).18 Of note, the well-established permissiveness of a proportion of these HLA-DPB1 mismatches and its relationship with TR reper- toire characteristics is also of interest and this is currently under investigation.19 The delayed reconstitution of this T- cell compartment might pose methodological challenges for TR repertoire analyses, but that and its central role in the co-ordination of effective immune, as well as alloreac- tive responses, warrant special attention. Finally, while Link-Rachner et al. focus their attention on the TRα reper- toire post HSCT, it would be interesting to assess whether the TRα and TRb repertoires follow similar, complementa- ry, or independent dynamics after different transplant set- tings. Parallel analysis of both chains, and potentially even attempting to determine their pairing with recent novel high-throughput approaches,20 is likely to give an even more complete picture of TR immune reconstitution with clinical and translational relevance.
Overall, the study by Link-Rachner et al. illustrates how the power of NGS has revolutionized the assessment of immune repertoires and opened a broad spectrum of pos- sibilities for unprecedented analysis of T-cell dynamics in the field of HSCT. Future studies building on this and other earlier pioneering work in this still developing field are called for to fully embrace this potential to enrich our understanding of T-cell immune reconstitution after HSCT. This knowledge should ultimately serve the objec- tive of promoting the regeneration of a healthy TR reper- toire that contributes both to the eradication of the under- lying disease and to the control of transplant-related mor- bidities, maximizing the therapeutic potential of allo- geneic HSCT.
Acknowledgments
This contribution was supported by grants from the Deutsche José Carreras Leukämie Stiftung (DJCLS R 15/02 and DJCLS R/2017), Dr. Werner Jackstädt Stiftung, and the Josef Senker Stiftung.
References
1 Link-Rachner CS, Eugster A, Rucker-Braun E, et al. T cell receptor alpha repertoire of CD8+ T cells following allogeneic stem cell trans- plantation using next-generation sequencing. Haematologica. 2019;104(3):622-631.
2. Qi Q, Liu Y, Cheng Y, et al. Diversity and clonal selection in the human T-cell repertoire. Proc Natl Acad Sci U S A. 2014;111(36): 13139-13144.
3. RosatiE,DowdsCM,LiaskouE,HenriksenEKK,KarlsenTH,Franke A. Overview of methodologies for T-cell receptor repertoire analysis.
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