期刊
JOURNAL OF IMMUNOLOGY
卷 193, 期 9, 页码 4356-4367出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1400389
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资金
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Science Technology Agency
- Grants-in-Aid for Scientific Research [26461464, 25860363, 25293223] Funding Source: KAKEN
Essential roles of NF-kappa B-inducing kinase (NIK) for the development of medullary thymic epithelial cells (mTECs) and regulatory T cells have been highlighted by studies using a strain of mouse bearing a natural mutation of the NIK gene (aly mice). However, the exact mechanisms underlying the defect in thymic cross-talk leading to the breakdown of self-tolerance in aly mice remain elusive. In this study, we demonstrated that production of regulatory T cells and the final maturation process of positively selected conventional alpha beta T cells are impaired in aly mice, partly because of a lack of mature mTECs. Of note, numbers of thymic dendritic cells and their expression of costimulatory molecules were also affected in aly mice in a thymic stroma-dependent manner. The results suggest a pivotal role of NIK in the thymic stroma in establishing self-tolerance by orchestrating cross-talk between mTECs and dendritic cells as well as thymocytes. In addition, we showed that negative selection was impaired in aly mice as a result of the stromal defect, which accounts for the development of organ-specific autoimmunity through a lack of normal NIK.
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