期刊
EMBO REPORTS
卷 19, 期 12, 页码 -出版社
WILEY
DOI: 10.15252/embr.201846303
关键词
MDA5; negative selection; RNA editing; spontaneous colitis; T cell maturation
资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [25293201, 25110719, 16H06279, 18K15186, 15K19126, 255768, 18K11526, 15K00401]
- Takeda Science Foundation
- SENSHIN Medical Research Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Nagao Memorial Fund
- Victorian Cancer Agency Mid-Career Fellowship
T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 (ADAR1) is the enzyme responsible for adenosine-to-inosine RNA editing in dsRNAs, and loss of ADAR1 activates the innate immune sensing response via melanoma differentiation-associated protein 5 (MDA5), which interprets unedited dsRNA as non-self. Although ADAR1 is highly expressed in the thymus, its role in the adaptive immune system, especially in T cells, remains elusive. Here, we demonstrate that T cell-specific deletion of Adar1 in mice causes abnormal thymic T cell maturation including impaired negative selection and autoimmunity such as spontaneous colitis. This is caused by excessive expression of interferon-stimulated genes, which reduces T cell receptor (TCR) signal transduction, due to a failure of RNA editing in ADAR1-deficient thymocytes. Intriguingly, concurrent deletion of MDA5 restores thymocyte maturation and prevents colitis. These findings suggest that prevention of MDA5 sensing of endogenous dsRNA by ADAR1-mediated RNA editing is required for preventing both innate immune responses and T cell-mediated autoimmunity.
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