Predictors for Recent Thymic Emigrant T Cell Reconstitution after Hematopoietic Cell Transplantation

Introduction Recent thymic emigrants (RTEs) are immature naïve T cells originating in the thymus, crucial for immune reconstitution after hematopoietic cell transplantation (HCT). Thymic damage may delay or permanently impair immune reconstitution. This study investigates variables influencing RTE reconstitution after HCT, aiming to identify factors essential for de novo immune reconstitution. Methods Immune monitoring (from day +14 to year +2) was performed on pediatric and young adult HCT patients transplanted between July 2020 and January 2023. In addition to standard immunophenotyping of major cell subsets, PBMCs were cryopreserved for in-depth T cell analysis using spectral flow cytometry. RTEs were phenotypically distinguished from naïve CD4+ T cells by the expression of CD62L and CD31. Baseline characteristics as well as graft versus host disease (GVHD), a known thymic damaging event, were correlated with RTE trajectory analysis and uni-/multivariable models. Results A total of 113 HCT patients were analyzed, with a median age at HCT of 12.7 years (range: 1 month to 28 years). Transplant types included 46 T-replete bone marrow (BM) (41%), 43 T-cell deplete (TCD) peripheral blood stem cells (38%), and 24 cord blood (CB; 21%). There were 49 cases of acute GVHD grade 2-4 (43%; 54% in CB, 39% in TCD, 41% in T-replete BM), 13 relapses (11%), and 1 transplant related mortality (<1%). Patients with grade 0 or 1 GVHD showed a progressive increase in RTE frequency from 90 days post-HCT, while patients with GVHD grade 2-4 exhibited delayed reconstitution initiation starting at 9-12 months or later (p=0.013; figure 1). Distribution of RTE levels were similar across all HCT types during the first 90 days, but TCD was associated with improved RTE reconstitution at day 180 compared to recipients of CB and T replete BM (p=0.025). Multivariate analysis showed patients over age 18 had reduced reconstitution at day 90 compared to younger patients (p<0.001). While no correlation was found between RTE counts and relapse, treatment related mortality, or overall survival, the occurrence of these events were limited. Conclusion Our study reveals distinct patterns of RTE reconstitution post-HCT. RTE reconstitution starts 90 days after HCT but is delayed by GvHD grade 2-4 possibly due to treatment related thymic injury, as well as in older patients. The timing and robustness of RTE recovery differs among graft types, with T-cell deplete patients exhibiting robust but delayed reconstitution. Larger cohorts are needed for further analysis, and to map RTE reconstitution and identify predictors (e.g., conditioning regimens, HCT complications).