Administration of RANKL boosts thymic regeneration upon bone marrow transplantation

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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.
Funding Information
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • Agence Nationale de la Recherche (ANR‐10‐INBS‐04‐01)
  • H2020 Marie Skłodowska-Curie Actions (CIG_SIGnEPI4Tol_618541)
  • Sir Jules Thorn Charitable Trust
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (AmbizionePZ00P3_131945)
  • Helmholtz-Gemeinschaft
  • Aix-Marseille Université

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