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<p>Systemic autoinflammatory diseases (SAID) with inborn errors of cell death (IECD) are caused by overactivation of programmed cell death (PCD). However, the pathogenesis by which PCD leads to autoinflammation remains unclear. Here, we identified IECD patients carrying compound heterozygous <i>RIPK1</i> variants K377E/R390G with autoinflammatory manifestations. Mechanistically, K377E and R390G mutations suppress NF-κB signaling and activate RIPK1 to promote cell death. CD8<sup>+</sup> T cells of the patients displayed overactivated RIPK1 and excessive cell death, leading to an elevated CD4/CD8 ratio, which could also be detected in patients with cleavage-resistant mutation of <i>RIPK1</i> or <i>SHARPIN</i> deficiency. We show that the increased cell death of CD8<sup>+</sup> T cells promotes TNF and IFN-γ secretion to activate monocytes/macrophages, which triggers overproduction of proinflammatory cytokines. In addition, disruption of the communication between T cells and monocytes/macrophages through pharmacologic blockade of TNF and IFN attenuates proinflammatory cytokine production in macrophages and relieves all the symptoms in patients. This study further clarifies the mechanism for a group of IECD with SAID. Increased CD4/CD8 ratio and augmented RIPK1 activation in T cells provide potentially additional criteria for diagnosis of RIPK1-dependent IECD and a combination of TNF/JAK inhibitor could be an effective therapy for the diagnosed patients.</p>

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CD8+ T cell loss induces autoinflammation in inborn errors of cell death

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Jialin Dai,
  • Taijie Jin,
  • Gaixiu Su,
  • Xu Han,
  • Jun Wang,
  • Chenlu Liu,
  • Wenjie Zheng,
  • Qiuye Zhang,
  • Ranran Zhang,
  • Hye Sun Kuehn,
  • Jun Yang,
  • Li Guo,
  • Dan Zhang,
  • Ming Li,
  • Yingjie Xu,
  • Tong Yue,
  • Min Wen,
  • Jia Zhu,
  • Min Kang,
  • Jianming Lai,
  • Feifei Wu,
  • Shihao Wang,
  • Jiahui Zhang,
  • Ivona Aksentijevich,
  • Sergio D. Rosenzweig,
  • Pui Y. Lee,
  • Junying Yuan,
  • Xiaomin Yu,
  • Qing Zhou

摘要

Systemic autoinflammatory diseases (SAID) with inborn errors of cell death (IECD) are caused by overactivation of programmed cell death (PCD). However, the pathogenesis by which PCD leads to autoinflammation remains unclear. Here, we identified IECD patients carrying compound heterozygous RIPK1 variants K377E/R390G with autoinflammatory manifestations. Mechanistically, K377E and R390G mutations suppress NF-κB signaling and activate RIPK1 to promote cell death. CD8+ T cells of the patients displayed overactivated RIPK1 and excessive cell death, leading to an elevated CD4/CD8 ratio, which could also be detected in patients with cleavage-resistant mutation of RIPK1 or SHARPIN deficiency. We show that the increased cell death of CD8+ T cells promotes TNF and IFN-γ secretion to activate monocytes/macrophages, which triggers overproduction of proinflammatory cytokines. In addition, disruption of the communication between T cells and monocytes/macrophages through pharmacologic blockade of TNF and IFN attenuates proinflammatory cytokine production in macrophages and relieves all the symptoms in patients. This study further clarifies the mechanism for a group of IECD with SAID. Increased CD4/CD8 ratio and augmented RIPK1 activation in T cells provide potentially additional criteria for diagnosis of RIPK1-dependent IECD and a combination of TNF/JAK inhibitor could be an effective therapy for the diagnosed patients.