AP-1 is a crucial transcription factor complex of TCR signaling, and it is well-established that TCR activation induces MAPK signaling,24 and accordingly, we found significantly upregulated MAPK signaling in all the lymphopenic states. cord blood CD4+ T-cell proliferation (< .05). Together, these findings suggest that reconstituting cord blood CD4+ T cells reflect the properties of fetal ontogenesis, and enhanced TCR signaling is responsible for the rapid restoration of the unique CD4+ T-cell biased adaptive immunity after cord blood transplantation. Visual Abstract Open in a separate window Introduction T-cell reconstitution in the early posttransplant period occurs through expansion of T cells carried with the graft and is driven by antigens and/or the posttransplant lymphopenic environment.1 This expansion of T cells in the lymphopenic environment is termed homeostatic proliferation.2 T-cell replete cord blood transplantation (CBT) results Bopindolol malonate in a rapid thymus-independent T-cell reconstitution, which is strikingly CD4+ biased compared with the well-established observation of CD8+ T-cell biased expansion after T-cell replete bone marrow transplant (BMT).3,4 In addition, a normal T-cell spectratype is observed as early as 30 days after a T-cell replete CBT.3 Conversely, in vivo T-cell depletion with antithymocyte globulin in CBT curbs this thymus-independent T-cell expansion, resulting in prolonged T-cell lymphopenia with late memory T-cell skewing.5,6 The distinct lymphocyte kinetics and a diverse T-cell repertoire after T-replete CBT is associated with antiviral reconstitution and potent antileukemic effect in the clinic.3,5,7-9 Further, we have demonstrated a robust antileukemic effect mediated by cord blood (CB) T cells compared with peripheral blood (PB) T cells in an in vivo animal model.10 CB T cells also appear much more sensitive than PB T cells to even small amounts of antithymocyte globulin.11 These observations suggest differential behavior of CB and PB T cells after HCT. Fetal and adult lymphocytes in birds, mammals, and humans have been described to have distinct ontogenetic origins.12,13 The fetal origin of CB T cells may endow them with an enhanced ability to fill the immunological void after HCT through processes involved in lymphopenia-induced proliferation such as T-cell receptor (TCR) or cytokine signaling.14-16 Hence, we questioned whether Bopindolol malonate early thymus-independent T-cell reconstitution after T-replete CBT recapitulates fetal T-cell ontogeny and, if so, whether upregulation of distinct cell signaling and biological processes could explain the enhanced T-cell proliferation after CBT. Methods Immune reconstitution The immune reconstitution study was approved by the Great Ormond Street Hospitals Institutional Review Board (protocol number 05/Q0508/61), and written informed consent was obtained from patients parents according to the Declaration of Helsinki. Serial monitoring of immune reconstitution was undertaken at 1, 2, and 6 months in 70 consecutive patients with T-cell replete transplant (30 CBT, 40 BMT). T-cell recovery was characterized by flow cytometry using fluorescein isothiocyanate or phycoerythrin-labeled Ab against CD3, CD4, and CD8. Transplant Rabbit Polyclonal to SFRS4 characteristics are shown in Table 1. Table 1. Demographics of cord blood and bone marrow recipients that contributed to the T-cell reconstitution study < .0001; Figure 1A). Despite the lower number of T cells carried with the CB grafts, we observed unprecedented thymus-independent expansion of the T-cell pool. The median T-cell count 2 months after CBT was 840 106/L (interquartile range, 575-1115) compared with a significantly lower median of 500 106/L (interquartile range, 280-980) after Bopindolol malonate BMT (Figure 1B). Open in a separate window Figure 1. Immune reconstitution after T-replete CBT and BMT. (A) Bar graph showing T-cells carried with a cord blood and a bone marrow graft. A median of 4 106/kg T cells are infused with a cord blood graft compared with 10 times more T cells (45 106/kg) infused with a bone marrow graft (< .0001). The bar graph represents the median, and error bars represent the 25th and 75th centiles. (B) Line graph showing T-cell reconstitution after T-replete CBT and BMT. Despite a 10 instances lower amount of T cells infused using the wire bloodstream graft, a considerably higher Bopindolol malonate Compact disc3+ T-cell recovery can be noticed 2 weeks post-CBT weighed against after BMT. (C-D) Line graph displaying Compact disc4+ and Compact disc8+ T-cell recovery after CBT and BMT, respectively. The T-cell recovery observed after T-replete CBT was CD4+ T-cell asymmetrically.