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