T-cell clonal dynamics determined by high resolution TCR-β sequencing in recipients after allogeneic hematopoietic cell transplantation

Abstract Delayed reconstitution of the immune system is a long-recognized complication after allogeneic hematopoietic cell transplantation (HCT). Specifically, loss of T-cell diversity has been thought to contribute to infectious complications, graft versus host disease (GVHD) and disease relapse. We performed serial high-resolution next generation sequencing of TCR-β in 99 related or unrelated donor (51 unrelated, 39 related) HCT (55 reduced intensity conditioning, 44 myeloablative conditioning) recipients during the first 3 months after HCT using the immunoSEQ ® Assay. We measured T-cell fraction, clonality (1- Peilou's eveness) and Daley-Smith richness from recipient samples at multiple time points. In agreement with prior studies, we found that although absolute T-cell numbers recover relatively quickly after transplant, T-cell repertoire diversity remains diminished. Restricted diversity was associated with conditioning intensity, use of ATG, and donor type. Increased number of expanded clones compared to donor T-cell clones at Day +30 was associated with the incidence of acute GVHD (HR=1.11, p=5 × 10−5). Even after exclusion of the twelve patients who developed acute GVHD before Day +30, the association between acute GVHD and an increased clonal expansion at Day +30 remained (HR=1.098, p=0.041), indicating that increased clonal T-cell expansion preceded the development of acute GVHD. Our results highlight T-cell clonal expansion as a potential novel biomarker for acute GVHD that warrants further study.