期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 10, 页码 4075-4080出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1014178108
关键词
thymus; repertoire; costimulation
资金
- Ministry of Education, Culture, Science, Sports, and Technology of the Japanese Government
- Grants-in-Aid for Scientific Research [19059009, 20200069, 19059008, 22790458] Funding Source: KAKEN
Claudins (Clds) are crucial constituents of tight- junction strands in epithelial cells and have a central role in barrier functions. We show that Cld4 is unexpectedly expressed in normal thymic lymphocytes independently of tight junctions. The Cld4 expression was mostly confined to a portion of the CD4/CD8 double-positive (DP) cells. The proportion of Cld4+ DP cells was markedly increased in MHC-I(-/-)II(-/-)mice but decreased in Ror gamma(-/-)mice, and Cld4(+) DP cells contained higher levels of the rearranged Tcra transcripts involving the most distal Va and Ja segments than Cld4-DP cells. The Cld4 expression levels were reduced in E47-deficient mice in a gene dose-dependent manner, and ChIP analysis indicated that E2A and HEB were bound to the E-box sites of the putative Cldn4 promoter region. Functionally, Cld4 showed a potent T-cell receptor costimulatory activity by coligation with CD3. The Cld4 was distributed diffusely on the cell surface and associated with CD4/lck independently of CD3 in the resting thymocytes. However, Cld4 was strongly recruited to the immunological synapse on specific T-cell receptor engagement through antigen-presenting cells. In the fetal thymic organ culture, knockdown of Cldn4 resulted in the reduced generation of CD4/CD8 single-positive cells from the DP cells. These results suggest that Cld4 is induced by E-protein activity in the later stages of DP cells to increase the efficiency of positive selection, uncovering a hitherto unrecognized function of a Cld family protein.
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