Dapl1 controls NFATc2 activation to regulate CD8+ T cell exhaustion and responses in chronic infection and cancer

Lele Zhu, Xiaofei Zhou, Meidi Gu, Jiseong Kim, Yanchuan Li, Chun Jung Ko, Xiaoping Xie, Tianxiao Gao, Xuhong Cheng, Shao Cong Sun

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1165-1176
Number of pages12
JournalNature Cell Biology
Volume24
Issue number7
DOIs
StatePublished - Jul 2022

ASJC Scopus subject areas

  • Cell Biology

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