Journal
JOURNAL OF IMMUNOLOGY
Volume 186, Issue 9, Pages 5047-5057Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1003533
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Funding
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Science and Technology Agency
- Japanese Society for the Promotion of Science
- Institute for Enzyme Research
- University of Tokushima
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [21390298, 19059010, 22790931, 22021012, 22659097, 22791078, 21390148, 22659094] Funding Source: KAKEN
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It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-beta receptor (LT beta R), receptor activator for NF-kappa B (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 LT beta R signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LT beta R 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 LT beta R and CD40 signals. Thus, the LT beta R 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. The Journal of Immunology, 2011, 186: 5047-5057.
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