Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma

J Immunol. 2011 May 1;186(9):5047-57. doi: 10.4049/jimmunol.1003533. Epub 2011 Mar 25.


It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-β receptor (LTβR), receptor activator for NF-κB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain enigmatic. In this study, we show that the LTβR signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LTβR and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LTβR and CD40 signals. Thus, the LTβR signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD40 Antigens / metabolism
  • Cell Differentiation / immunology*
  • Embryo, Mammalian
  • Epithelial Cells / cytology*
  • Flow Cytometry
  • Gene Expression
  • Gene Expression Regulation
  • Immunohistochemistry
  • Lymphotoxin beta Receptor / metabolism*
  • Mice
  • Mice, Knockout
  • Organogenesis*
  • Receptor Activator of Nuclear Factor-kappa B / biosynthesis*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Self Tolerance / immunology
  • Signal Transduction*
  • Thymus Gland / cytology
  • Thymus Gland / embryology*
  • Thymus Gland / metabolism


  • CD40 Antigens
  • Ltbr protein, mouse
  • Lymphotoxin beta Receptor
  • Receptor Activator of Nuclear Factor-kappa B