FAMIN in dendritic cells biochemically restrains T cell priming

FAMIN is a purine nucleoside enzyme that was first identified in genome-wide association studies (GWAS) as increasing risk for Crohn’s disease (CD). Defects in the enzyme that result in loss of catalytic activity are the only known monogenic cause of Still’s disease, a severe autoinflammatory condition that predisposes for the risk of developing macrophage activation syndrome (MAS). MAS can be triggered by common viral infections and result in hyperactivation of T lymphocytes. The work presented in this thesis builds on the discovery that FAMIN-sufficient mice are protected against influenza A infection, with dendritic cell (DC)- dependent excessive activation of CD8⁺ T cell responses in their FAMIN-deficient counterparts. Loss of FAMIN activity in DCs was shown to result in increased priming of both CD4⁺ and CD8⁺ T cells both <i>in vitro</i> and <i>in vivo</i>, resulting in enhanced antigen-specific cytotoxicity, IFNg secretion, and T cell expansion. Here, we discovered that FAMIN controls the pace of membrane trafficking and DC antigen processing to restrain T cell priming via a cytosolic NADH/ NAD⁺-dependent mechanism. We describe wide-reaching metabolic defects resulting from loss of FAMIN activity, including in the core pathways of glycolysis and TCA cycle activity, as well as upstream changes in glucose, fatty acid and amino acid metabolism. Notably, depressed rates of glycolysis and oxidative phosphorylation DCs lacking FAMIN function were not responsible for increased T cell priming capacity. Instead, we find that FAMIN balances flux through adenine-guanine nucleotide interconversion cycles to maintain the cytosolic NADH/ NAD⁺ ratio. We found that FAMIN additionally regulates T cell priming by DCs directly through the enzyme’s purine nucleoside phosphorylase (PNP) activity, converting exogenous hypoxanthine to inosine that acts on the T cell adenosine 2A receptor (A_2AR). In summary, FAMIN is a multifunctional purine nucleoside enzyme enabling flux through purine interconversion pathways highly integrated with cytoplasmic and mitochondrial metabolism. In DCs, FAMIN acts as a biochemical checkpoint to restrain T cell priming and prevent autoimmunity and autoinflammation.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Ramshorn, Katharina

Advisor dc:contributor.advisor

• Kaser, Arthur

• Autoimmunity
• Crohn's disease
• Dendritic cells
• Immunometabolism
• Purine metabolism
• Still's disease
• T cell priming

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/02677634-c56a-4e3b-b81b-410153c1f16d/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.96561

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/349559