Zhu, LeleLeleZhuZhou, XiaofeiXiaofeiZhouGu, MeidiMeidiGuKim, JiseongJiseongKimLi, YanchuanYanchuanLiChun-Jung KoXie, XiaopingXiaopingXieGao, TianxiaoTianxiaoGaoCheng, XuhongXuhongChengSun, Shao-CongShao-CongSun2022-08-082022-08-082022-071465-73921476-4679https://scholars.lib.ntu.edu.tw/handle/123456789/616299CD8+ 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.enTRANSCRIPTION FACTOR NFAT; SUBSETS; SIGNATURE[SDGs]SDG3journal article10.1038/s41556-022-00942-8357734322-s2.0-85133184599WOS:000819264100002https://api.elsevier.com/content/abstract/scopus_id/85133184599https://www.scopus.com/inward/record.uri?eid=2-s2.0-85133184599&doi=10.1038%2fs41556-022-00942-8&partnerID=40&md5=f9fc8e09f842ffe717fd4dbbf182f1b0