CD226 maintains regulatory T cell phenotype stability and metabolism by the mTOR/Myc pathway under inflammatory conditions
Jingchang Ma,
Wei Hu,
Yitian Liu,
Chujun Duan,
Dongliang Zhang,
Yuling Wang,
Kun Cheng,
Lu Yang,
Shuwen Wu,
Boquan Jin,
Yuan Zhang,
Ran Zhuang
Affiliations
Jingchang Ma
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China
Wei Hu
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China; Department of Emergency, The Fifth Medical Center of Chinese PLA General Hospital, #100 Western 4th Ring Road, Beijing 100039, China
Yitian Liu
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China
Chujun Duan
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China; Institute of Medical Research, Northwestern Polytechnical University, #127 West Youyi Road, Xi’an, Shaanxi 710072, China
Dongliang Zhang
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China
Yuling Wang
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China
Kun Cheng
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China
Lu Yang
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China
Shuwen Wu
Institute of Medical Research, Northwestern Polytechnical University, #127 West Youyi Road, Xi’an, Shaanxi 710072, China
Boquan Jin
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China
Yuan Zhang
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China; Institute of Medical Research, Northwestern Polytechnical University, #127 West Youyi Road, Xi’an, Shaanxi 710072, China; Corresponding author
Ran Zhuang
Department of Immunology, Fourth Military Medical University, #169 West Changle Road, Xi’an, Shaanxi 710032, China; Institute of Medical Research, Northwestern Polytechnical University, #127 West Youyi Road, Xi’an, Shaanxi 710072, China; Corresponding author
Summary: 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.
