IκB Kinase ε Is an NFATc1 Kinase that Inhibits T Cell Immune Response

Summary Activation of nuclear factor of activated T cells (NFAT) is crucial for immune responses. IKKe is an IκB kinase (IKK)-related kinase, and the function of IKKe remains obscure in T cells, despite its abundant expression. We report that IKKe inhibits NFAT activation and T cell responses by promoting NFATc1 phosphorylation. During T cell activation, IKKe was transiently activated to phosphorylate NFATc1. Loss of IKKe elevated T cell antitumor and antiviral immunity and, therefore, reduced tumor development and persistent viral infection. IKKe was activated in CD8 + T cells of mice bearing melanoma or persistently infected with a model herpesvirus. These results collectively show that IKKe promotes NFATc1 phosphorylation and inhibits T cell responses, identifying IKKe as a crucial negative regulator of T cell activation and a potential target for immunotherapy.