Date Published: February 20, 2018
Publisher: Public Library of Science
Author(s): Shiyun Xiao, Wen Zhang, Nancy R. Manley, Taishin Akiyama.
The postnatal thymus is an efficient microenvironment for T cell specification and differentiation. B cells are also present in the thymus and have been recently shown to impact T cell selection, however, the mechanisms controlling B cell development in the thymus are largely unknown. In Foxn1lacZ mutant mice, down-regulation of Foxn1 expression in thymic epithelial cells beginning 1 week after birth caused a dramatic reduction of T progenitors and an increase of B cell progenitors. This time point is coincident with the switch from fetal to adult-type hematopoietic stem cells (HSCs), which is regulated by the Lin28-Let7 system. We hypothesize that the thymic environment might regulate this process to suppress fetal-type B cell development in the thymus. In this study we show that in the Foxn1lacZ thymus, although the down-regulation of Lin28 in thymocytes was normal, up-regulation of Let-7 was impaired. The failure to up-regulate Let-7 caused a transient increase of Arid3a in B precursors, which is known to promote fetal-type B cell fate. Over-expression of Lin28a in HSCs also reduced Let-7 and promoted Arid3a expression in BM and thymic B progenitors, increasing B cell production in the thymus. The level of Let-7 in thymic B progenitors was up regulated by in vitro co-culture with IL15, Vitamin-D3, and retinoic acid, thus down-regulating Arid3a to promote B cell differentiation. All of these signals were produced in thymic epithelial cells (TECs) related to Let-7 expression in thymic B progenitors, and down-regulated in Foxn1lacZ mutants. Our data show that signals provided by TEC control thymic B cell development by up-regulating Let-7, suppressing Arid3a expression in intrathymic progenitor B cells to limit their proliferation during the neonatal to adult transition.
Hematopoietic stem cells (HSCs) undergo a developmental program change during ontogeny including changes in hematopoiesis sites, self-renewal activities, gene expression profiles, lineage biases, and differential intrinsic properties and differentiation potentials [1–3]. Two distinguishable properties of HSCs have been defined as specific characteristics of fetal (FL-HSCs) and adult (BM-HSCs) [3,4]. The switch from fetal to adult type HSC profiles has been proposed to occur in the period between one to three weeks after birth [3–5]. Fetal and adult HSC types have also been shown to have different potential for differentiation in the thymus. For example, Vγ5+ γδ T cells can only be generated from FL-HSCs in fetal thymus, but not from BM-HSCs [6,7]. Also, IL7 is required for adult thymocyte development but not for the production of thymocytes during fetal thymopoiesis [8,9]. However, the total range of effects due to the switch of HSCs from fetal to adult type on the thymocytes development, and the cell autonomous and non-autonomous mechanisms controlling these differences, remain open questions.
The requirement for the thymic microenvironment in specifying T lineage commitment and thymocyte differentiation is well documented; however, its role in the development of B cells in the thymus is less well understood. Although it has been long known that B cells are present and can develop within the thymus [33–36], it is only recently that any in vivo evidence for functional significance has been identified [37,38]. Our data provide evidence for a critical role for the thymic microenvironment and in particular for TECs in providing signals required for B cell development, proliferation, and differentiation in the thymus. Our data show that TECs produce a variety of factors and signaling molecules that regulate multiple stages of thymic B cell development, including the pathways that both influence lineage specification and control the balance of proliferation and differentiation in thymic B cell progenitors. Specifically, we provide evidence that Let-7 up-regulation in the thymic B progenitors normally limits the generation of thymic B cells through the inhibition of Arid3a, and that this up-regulation requires FOXN1-dependent signals from the thymic epithelium.
Taken together, our data show that the thymic microenvironment, especially MHCIIhi mTECs, provides necessary signals to up-regulate Let-7 in the fetal type B progenitors in the neonatal thymus, thus controlling the development of thymic B progenitors specifically in the perinatal period, via down-regulation of Arid3a. This function is a critical component of regulating the balance of thymic production of T and B cells during the switch from fetal to adult type progenitors during the neonatal to adult transition. However, this high level of Let-7 is not required to suppress thymic B cell production from adult-type BM derived TSPs. Given the broad regulatory effects of Lin28/Let-7, and the role of thymic B cells in central tolerance, our findings have potential implications for improving the transplantation of umbilical cord blood cells or adult BM cells, autoimmune disease, and for understanding the contributions of microenvironmental signals in cancer formation due to the disorder of Lin28/Let-7 axis .