Early-life thymectomy leads to an increase of granzyme-producing ?d T cells in children with congenital heart disease

Congenital heart disease (CHD) is the most common birth defect in newborns, often requiring cardiac surgery with concomitant thymectomy that is known to increase disease susceptibility later in life. Studies of ?d T cells, which are one of the dominant T cells in the early fetal human thymus, are rare. Here, we provide a comprehensive analysis of the ?d T cell compartment via flow cytometry and next-generation sequencing in children and infants with CHD, who underwent cardiac surgery shortly after birth. A perturbation of the ?d T cell repertoire is evident and Vd1 T cell numbers are reduced. However, those cells that are present, do retain cytotoxicity. In contrast, GZMA+CD28+CD161hi innate effector V?9Vd2 T cells are found in higher proportions. TCR-seq identifies an increase in TRDJ3+ ?d T cell clones in children with CHD, but not in a confirmatory group of neonates prior to CHD surgery, which overall points to a persistence of fetal-derived effector ?d T cells in children with CHD. Overall design: We aim to investigate the transcriptional profiles of T cells in children with CHD after thymectomy. To this end, scRNA-seq was performed on peripheral blood T cells from 5-12-year-old children with CHD who received thymectomy early after birth (CHD, n = 4, old_CHD) and control children (ctrl, n = 4, old_Ctrl). Next, to elucidate the impact of congenital heart surgery with concomitant removal of thymic tissue on the postnatal maturation of T cells within the first 6 months of life, we performed scRNA-seq of isolated peripheral blood T cells from two longitudinally followed infants with CHD before (Baseline, BSL, on day 8 and 9 of life, HLM139_1 and HLM140_1) and six months after surgery (Follow-up, FU, at day 188 and 189 of life, HLM139_2 and HLM140_2)