Fractal organization of the human T cell repertoire in health and after stem cell transplantation.

T cell repertoire diversity is generated in part by recombination of variable (V), diversity (D), and joining (J) segments in the T cell receptor ß (TCR) locus. T cell clonal frequency distribution determined by high-throughput sequencing of TCR ß in 10 stem cell transplantation (SCT) donors revealed a fractal, self-similar frequency distribution of unique TCR bearing clones with respect to V, D, and J segment usage in the T cell repertoire of these individuals. Further, ranking of T cell clones by frequency of gene segment usage in the observed sequences revealed an ordered distribution of dominant clones conforming to a power law, with a fractal dimension of 1.6 and 1.8 in TCR ß DJ and VDJ containing clones in healthy stem cell donors. This self-similar distribution was perturbed in the recipients after SCT, with patients demonstrating a lower level of complexity in their TCR repertoire at day 100 followed by a modest improvement by 1 year post-SCT. A large shift was observed in the frequency distribution of the dominant T cell clones compared to the donor, with fewer than one third of the VDJ-containing clones shared in the top 4 ranks. In conclusion, the normal T cell repertoire is highly ordered with a TCR gene segment usage that results in a fractal self-similar motif of pattern repetition across levels of organization. Fractal analysis of high-throughput TCR ß sequencing data provides a comprehensive measure of immune reconstitution after SCT.

Distinct oligoclonal T cells are associated with graft versus host disease after stem-cell transplantation.

BACKGROUND: In patients with hematologic malignancies who receive stem-cell transplantation, donors' T cells can recognize minor histocompatibility antigens on recipient cells and generate an objective response against the tumor. However, a major side effect of such therapy is graft-versus-host disease (GVHD). The purpose of this study was to characterize distinct T-cell clones that were frequently and exclusively involved in GVHD or graft-versus-tumor (GVT) effects. METHODS: We hypothesized that distinct GVHD-associated T-cell clones can be identified during the disease progression. To test this, we conducted comparative analysis of T-cell receptor (TCR) Vßs in donor-recipient pairs of patients with GVHD versus those with GVHD-free and relapse-free survival using quantitative reverse-transcriptase polymerase chain reaction and spectratyping analyses. RESULTS: We identified three sets of T-cell clones that were either frequently involved in GVHD (TCR Vß4, 11, and 23) or GVT effect (TCR Vß9, 16, and 20), or were increased at the time of GVHD and GVT effects in a patient-specific manner (TCR Vß2, 3, 7, 12, 15, and 17). Spectratyping analysis showed restricted clonality of the identified TCR Vßs. Polymerase chain reaction analysis also confirmed the presence of GVHD-associated T-cell clones at the site of the disease. CONCLUSIONS: These data suggest that GVHD- and GVT-associated clones can be distinguished by molecular analysis of TCR Vß to develop targeted therapy for GVHD.