期刊
INTERNATIONAL IMMUNOLOGY
卷 34, 期 1, 页码 45-52出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxab098
关键词
lymphotoxin; mTEC; self-antigen; thymic epithelial cell; thymus
类别
资金
- Japan Society for Promotion of Science (JSPS) [KAKENHI 21J11071, 19J00248, 19K16602, 16H05202, 17H05788, 19H03485, 19H04802, 15H05703]
- CREST Program of the Japan Agency for Medical Research and Development (AMED) [21gm1210008]
- Ichiro Kanehara Foundation for the Promotion of Medical Science and Medical Care [57]
- Astellas Foundation for Research on Metabolic Disorders [1102]
- JSPS Research Fellowship for Young Scientists
- World-leading INnovative Graduate Study Program for Life Science and Technology (WINGS-LST) of the University of Tokyo
- MD Scientist Training Program of the University of Tokyo
- Grants-in-Aid for Scientific Research [19H03485, 19H04802, 19J00248, 19K16602, 15H05703, 17H05788, 16H05202] Funding Source: KAKEN
mTECs shape the thymic microenvironment by expressing TRAs, leading to T-cell development. Sox4 is crucial for the development of thymic tuft cells, showing a potential role in diversifying antigen expression within the thymic medulla.
Medullary thymic epithelial cells (mTECs) help shape the thymic microenvironment for T-cell development by expressing a variety of peripheral tissue-restricted antigens (TRAs). The self-tolerance of T cells is established by negative selection of autoreactive T cells that bind to TRAs. To increase the diversity of TRAs, a fraction of mTECs terminally differentiates into distinct subsets resembling atypical types of epithelial cells in specific peripheral tissues. As such, thymic tuft cells that express peripheral tuft cell genes have recently emerged. Here, we show that the transcription factor SRY-box transcription factor 4 (Sox4) is highly expressed in mTECs and is essential for the development of thymic tuft cells. Mice lacking Sox4 specifically in TECs had a significantly reduced number of thymic tuft cells with no effect on the differentiation of other mTEC subsets, including autoimmune regulator (Aire)(+) and Ccl21a(+) mTECs. Furthermore, Sox4 expression was diminished in mice deficient in TEC-specific lymphotoxin beta receptor (LT beta R), indicating a role for the LT beta R-Sox4 axis in the differentiation of thymic tuft cells. Given that Sox4 promotes differentiation of peripheral tuft cells, our findings suggest that mTECs employ the same transcriptional program as peripheral epithelial cells. This mechanism may explain how mTECs diversify peripheral antigen expression to project an immunological self within the thymic medulla.
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