Abstract
Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoiesis and a prolonged period of T‐cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, we show that RANK ligand (RANKL) is upregulated in CD4+ thymocytes and lymphoid tissue inducer (LTi) cells during the early phase of thymic regeneration. Importantly, whereas RANKL neutralization alters TEC recovery after irradiation, ex vivo RANKL administration during BMT boosts the regeneration of TEC subsets including thymic epithelial progenitor‐enriched cells, thymus homing of lymphoid progenitors, and de novo thymopoiesis. RANKL increases specifically in LTi cells, lymphotoxin α, which is critical for thymic regeneration. RANKL treatment, dependent on lymphotoxin α, is beneficial upon BMT in young and aged individuals. This study thus indicates that RANKL may be clinically useful to improve T‐cell function recovery after BMT by controlling multiple facets of thymic regeneration.
Highlights
The thymus controls the generation of a diverse repertoire of T lymphocytes
Because at steady state RANK ligand (RANKL) has been reported as a potent regulator of Medullary thymic epithelial cell (TEC) (mTECs) differentiation (Rossi et al, 2007; Hikosaka et al, 2008; Ohigashi et al, 2011), we investigated whether this cytokine plays a role in thymic regeneration
At d3 SL-total body irradiation (TBI), while the expression of Rankl mRNA was strongly upregulated in the WT thymus, no detectable increase of Rankl mRNA was observed in irradiated ZAP-70À/À thymus (Fig 1E)
Summary
The thymus controls the generation of a diverse repertoire of T lymphocytes. Cortical thymic epithelial cells (cTECs) support the differentiation of T-cell progenitors and the conversion of CD4+CD8+ double-positive (DP) thymocytes into CD4+CD8À and CD4ÀCD8+ single-positive (SP) cells (Anderson & Takahama, 2012). This complex interplay is referred to as thymic cross talk (van Ewijk et al, 1994; Lopes et al, 2015). Cytoablative treatments such as radiation or chemotherapy, used to prepare patients notably to bone marrow (BM) transplantation (BMT), severely affect hematopoietic cells and TECs, which results in delayed T-cell reconstitution (Adkins et al, 1988; van den Brink et al, 2004; Fletcher et al, 2009; Hollander et al, 2010). Alterations in TEC ultrastructure and a reduction in some stromal cells have been reported (Adkins et al, 1988; Irifune et al, 2004)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
