Dapl1 controls NFATc2 activation to regulate CD8+ T cell exhaustion and responses in chronic infection and cancer
Journal
Nature cell biology
Journal Volume
24
Journal Issue
7
Date Issued
2022-07
Author(s)
Zhu, Lele
Zhou, Xiaofei
Gu, Meidi
Kim, Jiseong
Li, Yanchuan
Xie, Xiaoping
Gao, Tianxiao
Cheng, Xuhong
Sun, Shao-Cong
Abstract
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.
Subjects
TRANSCRIPTION FACTOR NFAT; SUBSETS; SIGNATURE
SDGs
Publisher
NATURE PORTFOLIO
Type
journal article