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T-cell receptors following SCT
reconstitution following transplantation remains scarce. The recovery of neutrophil counts is achieved between day 14 and day 30 post transplantation. In contrast, reduced lymphocyte counts within the first 100 days fol- lowing transplantation and an associated delay in T-cell reconstitution have been reported.22 Consistent with this, only patients from two groups out of five in the current analysis achieved normal range lymphocytes by day 180.
T cells in transplanted patients primarily consisted of CD8+ T cells, contrasting the preferential CD4+-dominated composition of the healthy reference population. This inverse ratio of CD4+ and CD8+ T cells after transplanta- tion has been previously described. Our detailed analyses of CD8+ T-cell subsets revealed the dominance of memory cells (EM and TEMRA) and reduced naïve CD8+ T-cell fre- quencies. This finding is in line with previous reports demonstrating that following SCT, the T-cell compart- ment is mainly composed of memory cells with an associ- ated low recovery of naïve cells. The dominance of mem- ory cells is assumed to be based on the proliferation of T cells that were already present in the donor graft.13
In this context, the impact of in vivo T-cell depletion is of special interest, as we demonstrated the lowest naïve cell counts within these groups. The application of ATG prior to transplantation has been reported to impair the recon- stitution of naïve CD4+ and naïve CD8+ T cells for up to one year while not affecting the reconstitution of effector memory cells.23 Effects in patients receiving PTCy were described differently in prior studies. Approximately 70%
of memory and effector T cells were depleted by the application of cyclophosphamide, whereas naïve T cells were not affected by cyclophosphamide. The authors pro- posed that T-cell reconstitution is generated from naïve precursors with T cells acquiring an effector phenotype after antigen stimulation from naïve-derived T cells.24,25
Assessment of the dominant clonotypes revealed strik- ing differences between groups, with dominant clono- types in the naïve repertoire being highest in the groups receiving ATG and PTCy. The underlying mechanism for the enhanced clonal proliferation of naïve clonotypes under these conditions remains unknown. The participa- tion of antigen-specific naïve T cells in immune reconsti- tution following SCT has been described.25 These cells may stimulate the proliferation of certain T-cell clono- types in the naïve compartment. Furthermore, the pres- ence of stem cell-like memory T cells preceding the recon- stitution of effector cells following transplantation origi- nating from naïve T cells has been reported.25,26
The assumption that early immune reconstitution origi- nates from naïve precursors gives reason to expect that the memory repertoire is mirrored by clonotypes that are also present in the naïve compartment. In our samples, we determined that 51% and 63% (day 60 and day 180, respectively) of the memory repertoire was composed of clonotypes that were also found in the naïve compart- ment. Approximately 40-50% of the TRα memory reper- toire was not identified in the naïve compartment. Similar observations were previously described for TRb.13 The
A
B
Figure 5. Cytomegalovirus (CMV) and T-cell receptor alpha (TRα) diversity. (A) Clinical observations of the development of CMV reactivation (CMV, yes - no), acute graft-versus-host disease (aGvHD) and chronic GvHD (cGvHD). (B) Simpson’s diversity index (Ds) of the naïve and memory TRα repertoire of each patient on day 60 (60) and day 180 (180) post transplantation. Patients suffering from CMV reactivation close to the sampling point were mapped. Repertoire diversity is mapped in relation to CMV serostatus of the recipient (R) and donor (D). CMV seropositivity (+) and CMV seronegativity (-).
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