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A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Saveljeva, Svetlana 
Sewell, Gavin W 
Ramshorn, Katharina 
Cader, M Zaeem 
West, James A 

Abstract

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.

Description

Keywords

NADH/NAD(+) reductive stress, T cell priming, autoimmunity, dendritic cells, membrane trafficking, purine nucleotide cycle, Autoimmunity, CD8-Positive T-Lymphocytes, Dendritic Cells, Lymphocyte Activation, Purines

Journal Title

Cell Metab

Conference Name

Journal ISSN

1550-4131
1932-7420

Volume Title

34

Publisher

Elsevier BV
Sponsorship
European Research Council (260961)
Wellcome Trust (103077/Z/13/Z)
Wellcome Trust (106260/Z/14/Z)
European Research Council (648889)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
Academy of Medical Sciences (SGL018/1119)
Wellcome Trust (105920/Z/14/Z)
Wellcome Trust (102163/B/13/Z)
Wellcome Trust (216630/Z/19/Z)
MRC (MC_UU_00014/5)
Academy of Medical Sciences (SGL022\1008)
Wellcome Trust (222056/Z/20/Z)
Wellcome Trust (222497/Z/21/Z)