CD226 maintains regulatory T cell phenotype stability and metabolism by the mTOR/Myc pathway under inflammatory conditions

Regulatory T (Treg) cells exhibit immunosuppressive phenotypes and particular metabolic patterns with certain degrees of plasticity. Previous studies of the effects of the co-stimulatory molecule CD226 on Treg cells are controversial. Here, we show that CD226 primarily maintains the Treg cell stability and metabolism phenotype under inflammatory conditions. Conditional deletion of CD226 within Foxp3+ cells exacerbates symptoms in murine graft versus host disease models. Treg cell-specific deletion of CD226 increases the Treg cell percentage in immune organs but weakens their immunosuppressive function with a T helper 1-like phenotype conversion under inflammation. CD226-deficient Treg cells exhibit reduced oxidative phosphorylation and increased glycolysis rates, which are regulated by the adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/myelocytomatosis oncogene (Myc) pathway, and inhibition of Myc signaling restores the impaired functions of CD226-deficient Treg cells in an inflammatory disease model of colitis. This study reveals an Myc-mediated CD226 regulation of Treg cell phenotypic stability and metabolism, providing potential therapeutic strategies for targeted interventions of Treg cell-specific CD226 in inflammatory diseases. [Display omitted] •CD226 deficiency impairs Treg cell immunosuppressive functions under inflammation•CD226 deficiency makes Treg cells prone to a Th1-like phenotype•CD226 loss drives a metabolic shift of activated Treg cells from OXPHOS to glycolysis•CD226 regulates Treg cell stability and metabolism via Myc signaling Ma et al. demonstrate that CD226 maintains the phenotypic stability and metabolic preference of Treg cells through the AMPK/mTOR/Myc signaling pathway. CD226 deficiency in Treg cells causes an upregulation of Myc expression, resulting in Treg cells being more prone to glycolysis and a Th1-like phenotype with impaired inhibitory functions.