Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Cell Metab. 2022 Jan 4;34(1):106-124.e10. doi: 10.1016/j.cmet.2021.12.009.
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4 and CD8 T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.
斯蒂尔病是炎症与自身免疫并存的典范，易在病毒感染时引发细胞因子风暴，导致过度的 T 淋巴细胞激活。嘌呤核苷酶 FAMIN 的功能丧失是导致单基因斯蒂尔病的唯一已知原因。在这里，我们发现树突状细胞（DC）中的 FAMIN 激活嘌呤代谢物可抑制 CD4 和 CD8 T 细胞的启动。缺乏 FAMIN 活性的 DC 可增强抗原特异性细胞毒性、IFNγ 分泌和 T 细胞扩增，导致过度的甲型流感病毒特异性反应。功能减弱的 FAMIN-I254V 已经表现出增强的启动作用，约 6%的人类是纯合的。FAMIN 通过平衡腺嘌呤-鸟嘌呤核苷酸相互转化循环中的通量，以 NADH/NAD 依赖性的方式控制膜运输并抑制抗原呈递。FAMIN 还将次黄嘌呤转化为肌苷，DC 释放肌苷来抑制 T 细胞激活。因此，功能受损的 FAMIN 增强了对同种异体肿瘤的免疫监视。FAMIN 是一种生化检查点，可防止过度的抗病毒 T 细胞反应、自身免疫和自身炎症。
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