title: IκB Kinase ε Is an NFATc1 Kinase that Inhibits T Cell Immune Response.
abstract: Activation of nuclear factor of activated T cells (NFAT) is crucial for immune responses. IKKε is an IκB kinase (IKK)-related kinase, and the function of IKKε remains obscure in T cells, despite its abundant expression. We report that IKKε inhibits NFAT activation and T cell responses by promoting NFATc1 phosphorylation. During T cell activation, IKKε was transiently activated to phosphorylate NFATc1. Loss of IKKε elevated T cell antitumor and antiviral immunity and, therefore, reduced tumor development and persistent viral infection. IKKε was activated in CD8(+) T cells of mice bearing melanoma or persistently infected with a model herpesvirus. These results collectively show that IKKε promotes NFATc1 phosphorylation and inhibits T cell responses, identifying IKKε as a crucial negative regulator of T cell activation and a potential target for immunotherapy.
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA; Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Feldman
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Akbari
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tibbetts
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. Electronic address: pinghui.feng@med.usc.edu.
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D045744:Cell Line, Tumor; D006224:Cricetinae; D006566:Herpesviridae Infections / Q000201:enzymology / Q000276:immunology; D051550:I-kappa B Kinase / Q000502:physiology*; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology; D008647:Mesocricetus; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D017735:Virus Latency
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D051550:I-kappa B Kinase; C496566:Ikbke protein, mouse