Stem cell source-dependent reconstitution of FOXP3+ T cells after pediatric SCT and the association with allo-reactive disease

Abstract

In adult patients, regulatory CD4 þ FOXP3 þ T cells are suggested to have a role in the control of allo-reactive disease after hematopoietic SCT (HSCT). We compared CD4 þ FOXP3 þ T-cell reconstitution after unrelated cord blood (UCB), matched unrelated donor (MUD) and matched sibling donor (MSD) HSCT in children, starting as early as 1 week after transplantation, and analyzed the association with allo-reactive disease. A total of 30 children were included who underwent a myeloablative-conditioning regimen followed by UCB (12/30), MUD (7/30) or MSD (11/30) HSCT. These three patient groups showed significant differences in FOXP3 þ T-cell reconstitution pattern. Early after UCB and MSD, but not after MUD, HSCT a peak in FOXP3 þ T cells was observed. There were significant differences in activation status and Ki67 expression of the FOXP3 þ T cells after UCB and MSD, respectively. FOXP3 þ T-cell proportions early after HSCT and in the graft were inversely correlated with allo-reactivity. This study indicates that FOXP3 reconstitution after HSCT is dependent on the type of graft used. Furthermore, in children evaluation of FOXP3 þ T-cell numbers early after HSCT and in the graft may be used to judge the risk of developing allo-reactivity after HSCT.

Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation

“…They are critical in controlling responses from other immune cell subsets to self and foreign antigens, and play a central role in preventing autoimmune disease. Tregs can be subdivided into naturally occurring Tregs, derived from the thymus, and induced Tregs, which are differentiated from nonregulatory CD4 + CD25 + cells [1,57]. Induced Tregs are more susceptible to apoptosis and have a less stable expression of FoxP3 [57].…”

“…Reconstitution of Tregs has been suggested to be primarily achieved by HPE without major contribution of thymopoiesis, especially compared to reconstitution of effector T cells [18,51,62,65]. The proportion of Tregs among the CD4 + T cell population returns to normal within 6 weeks post-HCT, as soon as the CD4 + T cells are detectable [57,60]. In the subsequent 2 to 3 months, differences in the stability of this proportion have been observed [57,60], which might be related to a higher proportion of activation-induced Tregs, the occurrence of GvHD (and associated treatment) and thymopoiesis.…”

“…Notably, the exact mechanisms of Cy prophylaxis in humans still need to be elucidated. Despite differences in stability after one-month, normal levels of Tregs are achieved by 9 months post-HCT [18,57,60]. In patients with prolonged CD4 + lymphopenia, however, Treg levels were observed to decline after 9 months and remain at very low levels from 12-24 months [18,62].…”

Immune Reconstitution after Allogeneic Hematopoietic Cell Transplantation in Children

“…A limited number of studies described reconstitution of FoxP3 þ Tregs after UCBT and BMT, which takes 1 to 6 weeks for both sources, even with ATG in the conditioning [20,30] (Table 2). When comparing UCB, sibling BM, and unrelated BM transplantations, Treg reconstitution after UCBT and sibling BMT is much faster than after unrelated BMT [30]. The results in UCBT may be associated with the finding that fetal T cells more easily develop into Tregs than adult T cells [67].…”

Pre-transplantation thymic function is associated with the risk of acute graft versus host disease and cytomegalovirus viremia after allogeneic hematopoietic stem cell transplantation

“…The negative selection relies on the ectopic expression of tissue-restricted peripheral self-antigens (TRA) in mature medullary thymic epithelial cells, which may be damaged in patients with impaired thymic function, thus, lead to compromised negative selection and GVHD [27,29]. Moreover, another mechanism relevant to thymic function could implicate donor-derived CD4 CD25high regulatory T (Treg)-cell reconstitution [30,31]. Those cells were also selected in the thymus, a competent thymic is needed for regulatory T-cells recovery in AHSCT patients [32].…”