RIPK1 Biallelic Activating Variants lead to Autoinflammatory Disease Driven by T cell Death

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key regulator of cell fate decision between pro-survival signaling and programmed cell death. The activation of RIPK1 is extensively modulated by posttranslational modification, such as ubiquitination. RIPK1 overactivation mediates autoinflammatory diseases in humans. However, the role of RIPK1 ubiquitination in human autoinflammatory diseases has not been reported, and the mechanism mediating the interaction of cell death and autoinflammation is largely unknown. Here, we report two patients carrying compound heterozygous RIPK1 variants K377E/R390G with recurrent fevers, lymphadenopathy and skin rashes. Mechanistically, K377E and R390G mutations impaired ubiquitination of RIPK1, which suppresses the formation of TNFR1 signaling complex (TNF-RSC) and NF-κB activation, resulting in the loss of CD8 ⁺ T cells mediated by RIPK1 activation-induced cell death in the patients. We reveal that the death of CD8 ⁺ T cells promotes the secretion of TNF and IFNγ to activate monocytes and macrophages, which triggers further production of proinflammatory cytokines to amplify autoinflammation. Disruption of the communication between T cells and monocytes/macrophages through pharmacologic blockade of TNF and IFNγ attenuated proinflammatory cytokine production in macrophages. Collectively, our results demonstrate a crucial role of RIPK1 ubiquitination in regulating CD8 ⁺ T cell death and restraining autoinflammation. Our study demonstrates the mechanism for a group of autoinflammatory diseases mediated by RIPK1 activation-induced cell death, and highlights an important role of CD8 ⁺ T cells in driving autoinflammation.