CD31 regulates metabolic switch in Treg migration attenuates rheumatoid arthritis
Abstract CD31 (PECAM‐1) plays a critical role in T cell migration, whilst its immunoreceptor tyrosine inhibitory motifs (ITIMs), Y663 and Y686, are recognised for their roles in endothelial function, the precise mechanism in regulating immune cell remains elusive. Here, we demonstrate that CD31 is e...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-08-01
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| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.70441 |
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| Summary: | Abstract CD31 (PECAM‐1) plays a critical role in T cell migration, whilst its immunoreceptor tyrosine inhibitory motifs (ITIMs), Y663 and Y686, are recognised for their roles in endothelial function, the precise mechanism in regulating immune cell remains elusive. Here, we demonstrate that CD31 is essential for Treg migration. Upon ITIM engagement, CD31 activates and interacts with the protein tyrosine phosphatase SHP2. In vivo, CD31 Y663F gene transfer recapitulates the wild‐type migration phenotype, driven by a metabolic switch to fructose utilisation under the regulation of the PFKFB3 gene. Conversely, the Y686F mutation impairs Tregs migration by disrupting both glycolysis and the switch to fructose metabolism, thus promoting the mitochondrial function via activation of the RNF111/OGT pathway. Our findings reveal a novel role for CD31 ITIMs in orchestrating a metabolic that is switch crucial for Treg migration. This understanding of CD31 polymorphisms and their impact on Treg migration offers potential therapeutic avenues for autoimmune diseases, particularly rheumatoid arthritis (RA). Key points CD31 Y663F‐mutant Tregs exhibit a glucose‐to‐fructose metabolic shift, characterised by reduced glucose uptake and enhanced fructose utilisation regulated by PFKFB3. CD31 Y686F mutation disrupts both glycolysis and fructose metabolism in Tregs, shifting energy production towards mitochondrial function via the RNF111/OGT pathway. These findings highlight a novel mechanism by which CD31 ITIMs control Treg migration, offering new therapeutic targets for autoimmune diseases such as RA. |
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| ISSN: | 2001-1326 |