Administration of RANKL boosts thymic regeneration upon bone marrow transplantation

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.

A B D E C Figure EV2. TECs but not fibroblasts and LTi cells are severely reduced in LTa À/À mice at d3 SL-TBI.
A, B Histograms show numbers of cTECs and mTECs (A) as well as mTEC subsets (B) in WT and LTa À/À mice at d3 SL-TBI. C Thymic sections from WT and LTa À/À mice at d3 SL-TBI were stained for the expression of K14 and Aire. The histogram shows the density of Aire + cells in medullary area. m, medulla. Fifteen sections were quantified; scale bar: 100 lm. D The histogram shows numbers of CD45 À PDFRa + fibroblasts in WT and LTa À/À mice at d3 SL-TBI. E Flow cytometry profiles and frequencies of thymic LTi cells from WT or LTa À/À mice at d3 SL-TBI.
Data information: Data are shown as mean AE SEM and are pooled of two independent experiments with similar results (n = 3-5 mice per group). *P < 0.05; **P < 0.01; one-tailed Mann-Whitney U-test. Exact P-values are provided in Appendix Table S2.
EMBO Molecular Medicine ª 2017 The Authors Figure EV4. RANKL treatment early after BMT boosts peripheral T-cell reconstitution optimally in an LTa-dependent manner.
Data information: Data are shown as mean AE SEM and are pooled of two independent experiments with similar results (n = 3 mice per group). *P < 0.05; **P < 0.01; one-tailed Mann-Whitney U-test. Exact P-values are provided in Appendix Table S2.
EMBO Molecular Medicine ª 2017 The Authors