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A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.

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cam.depositDate2021-12-09
cam.orpheus.successTue Feb 01 19:02:26 GMT 2022 - Embargo updated*
cam.orpheus.successVoR added.
dc.contributor.authorSaveljeva, Svetlana
dc.contributor.authorSewell, Gavin William
dc.contributor.authorRamshorn, Katharina
dc.contributor.authorCader, Mohammed
dc.contributor.authorWest, James A
dc.contributor.authorClare, Simon
dc.contributor.authorHaag, Lea-Maxie
dc.contributor.authorde Almeida Rodrigues, Rodrigo Pereira
dc.contributor.authorUnger, Lukas W
dc.contributor.authorIglesias-Romero, Ana Belén
dc.contributor.authorHolland, Lorraine M
dc.contributor.authorBourges, Christophe
dc.contributor.authorMd-Ibrahim, Muhammad N
dc.contributor.authorJones, James Owain
dc.contributor.authorBlumberg, Richard S
dc.contributor.authorLee, James C
dc.contributor.authorKaneider, Nicole C
dc.contributor.authorLawley, Trevor D
dc.contributor.authorBradley, Allan
dc.contributor.authorDougan, Gordon
dc.contributor.authorKaser, Arthur
dc.contributor.orcidCader, Mohammed [0000-0002-4121-748X]
dc.date.accessioned2021-12-11T00:30:16Z
dc.date.available2021-12-11T00:30:16Z
dc.date.issued2022-01-04
dc.date.updated2021-12-09T09:14:38Z
dc.description.abstractStill'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.
dc.identifier.doi10.17863/CAM.78780
dc.identifier.eissn1932-7420
dc.identifier.issn1550-4131
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331332
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.departmentDepartment of Medicine
dc.rightsAttribution 4.0 International (CC BY)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleA purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
dc.typeArticle
dcterms.dateAccepted2021-12-08
prism.publicationNameCell Metab
pubs.funder-project-idEuropean Research Council (260961)
pubs.funder-project-idWellcome Trust (103077/Z/13/Z)
pubs.funder-project-idWellcome Trust (106260/Z/14/Z)
pubs.funder-project-idEuropean Research Council (648889)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
pubs.funder-project-idAcademy of Medical Sciences (SGL018/1119)
pubs.funder-project-idWellcome Trust (105920/Z/14/Z)
pubs.funder-project-idWellcome Trust (102163/B/13/Z)
pubs.funder-project-idWellcome Trust (216630/Z/19/Z)
pubs.funder-project-idMRC (MC_UU_00014/5)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.cmet.2021.12.009

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