Identification of Trim29 as a Key checkpoint inhibitor of natural killer cell functions

Abstract Natural killer (NK) cells play an important role in immune surveillance and protective immunity, mainly through rapid cytokine release and cytolytic activities. But how such responses are regulated remains poorly defined. Here, we demonstrated that E3 ubiquitin ligase Trim29 is a crucial regulator of NK cell functions. NK cells lacking Trim29 show increased production of IFN-γ. NK cell-derived IFN-γ has previously been demonstrated to be protective against murine cytomegalovirus (MCMV) infection, and we show here that Trim29−/− mice as well as Trim29lox/loxNKp46-iCre mice exhibit decreased hepatic viral load upon challenge with MCMV, indicating that Trim29 acts within NK cells to regulate antiviral responses. In addition, we discovered that Trim29 is up-regulated in activated NK cells during MCMV infection in response to signals from the proinflammatory cytokines IL-12 and IL-18. Mechanistically, Trim29 suppresses NK cell IFN-γ expression by ubiquitinating the TGF-β activated kinase 1 binding protein 2 (TAB2). These results identify TRIM29 as a previously unknown regulator that restricts NK cell functions.