Ting, Adrian T

Cytotoxic T cells produce the cytokine interferon-γ (IFN-γ). We sought to determine whether IFN-γ directly kills target cells and found that T cells used IFN-γ to kill murine melanoma cells lacking the kinases TBK1 and IKKε. In the absence of both kinases, IFN-γ induced the production of TNF receptor 1 (TNFR1) and the sensor Z-DNA binding protein 1 (ZBP1) in the tumor cells to stimulate receptor-interacting protein kinase 1 (RIPK1)–dependent apoptosis in a cell-autonomous manner. IFN-γ also enhanced the activation of nuclear factor κB (NF-κB) signaling in a TNFR1-dependent manner in cells deficient in both TBK1 and IKKε. Because IFN-γ–induced apoptosis occurred in a transcription-dependent manner with slow kinetics, STAT1 and NF-κB cooperated to activate the expression of inflammatory genes in the dying cells. Thus, IFN-γ–induced cell death was accompanied by an inflammatory signature in the absence of TBK1 and IKKε. TBK1 and IKKε not only mediated the induction of type I IFN but also inhibited RIPK1-dependent death and NF-κB–dependent inflammation. Therefore, we propose that these kinases may have gained these intertwined functions so that cells infected by pathogens that produce antagonists of TBK1 and IKKε are eliminated by IFN-γ–secreting T cells in an inflammatory manner to compensate for the inhibition of type I IFN production.

Significance The mechanisms underlying inflammatory disorders are poorly understood. In this study, we show that inappropriate cell death may cause uncontrolled inflammation. We found that CYLD, an enzyme that removes K63-linked polyubiquitination, is normally inhibited. But in the cpdm mouse strain that has a loss-of-function in the Sharpin gene, the brake on CYLD is no longer present. When CYLD is no longer inhibited, it turns on death signaling in cells exposed to the cytokine TNF, and the ensuing inappropriate cell death causes skin inflammation and other immune disorders in the cpdm mouse. Removing CYLD from the cpdm mouse prevents cell death and reverses the inflammation. We conclude that excessive CYLD activity leads to inappropriate cell death and inflammation.