期刊
NATURE CELL BIOLOGY
卷 24, 期 7, 页码 1165-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41556-022-00942-8
关键词
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类别
资金
- NIH/NCI Cancer Center Support Grant (CCSG) [P30CA016672]
- NIH [1S10OD024977-01, AI64639]
- China Scholarship Council [201906380080]
- [CA016672]
This study identified Dapl1 as a crucial regulator of CD8(+) T cell immunity, showing that Dapl1 deficiency can lead to functional exhaustion of CD8(+) T cells in chronic infection and cancer.
CD8(+) T cells are central mediators of immune responses against infections and cancer. Here we identified Dapl1 as a crucial regulator of CD8(+) T cell responses to cancer and infections. Dapl1 deficiency promotes the expansion of tumour-infiltrating effector memory-like CD8(+) T cells and prevents their functional exhaustion, coupled with increased antitumour immunity and improved efficacy of adoptive T cell therapy. Dapl1 controls activation of NFATc2, a transcription factor required for the effector function of CD8(+) T cells. Although NFATc2 mediates induction of the immune checkpoint receptor Tim3, competent NFATc2 activation prevents functional exhaustion of CD8(+) T cells. Interestingly, exhausted CD8(+) T cells display attenuated NFATc2 activation due to Tim3-mediated feedback inhibition; Dapl1 deletion rescues NFATc2 activation and thereby prevents dysfunction of exhausted CD8(+) T cells in chronic infection and cancer. These findings establish Dapl1 as a crucial regulator of CD8(+) T cell immunity and a potential target for cancer immunotherapy.
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