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

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. [Display omitted] •IKKε is activated during T cell activation•IKKε phosphorylates NFATc1 and inhibits NFAT activation•Loss of IKKε elevates T cell responses against viral infection and tumor development•IKKε is constitutively activated in tumor-bearing or persistently infected mice Zhang et al. identify a negative feedback mechanism in which IKKε promotes NFATc1 phosphorylation to inhibit T cell responses. IKKε deficiency in mice leads to increased antiviral and antitumor T cell immunity and decreased persistent viral infection and tumor development.