A purine metabolic checkpoint that prevents autoimmunity and autoinflammation
Authors list
Svetlana Saveljeva Gavin W Sewell Katharina Ramshorn M Zaeem Cader James A West Simon Clare Lea-Maxie Haag Rodrigo Pereira de Almeida Rodrigues Lukas W Unger Ana Belén Iglesias-Romero Lorraine M Holland Christophe Bourges Muhammad N Md-Ibrahim James O Jones Richard S Blumberg James Lee Nicole C Kaneider Trevor D Lawley Allan Bradley Gordon Dougan Arthur KaserAbstract
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.
Journal details
Journal Cell Metabolism
Volume 34
Issue number 1
Pages 106-124.e10
Available online
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Publisher website (DOI) 10.1016/j.cmet.2021.12.009
Europe PubMed Central 34986329
Pubmed 34986329
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