Jifeng Zhang1, Lei Zhao2, Jing Wang3, Zhihua Cheng4, Mengyao Sun4, Jiayi Zhao5, Bin Liu2, Xiyu Liu6, Zhenke Wen7, Zhibo Li2. 1. Jilin University School of Pharmaceutical Sciences, Changchun, China. 2. Second Hospital of Jilin University, Changchun, China. 3. Changchun Central Hospital, Changchun, China. 4. First Hospital of Jilin University, Changchun, China. 5. General Hospital of Jilin Chemical Group Corporation, Jilin, China. 6. China-Japan Union Hospital of Jilin University, Changchun, China. 7. Soochow University, Suzhou, China.
Abstract
OBJECTIVE: Takayasu arteritis (TAK) is a progressive autoimmune large vessel vasculitis with infiltration of proinflammatory T cells, with a largely unknown etiology. This study was undertaken to explore the involvement of mechanistic target of rapamycin (mTOR) in proinflammatory T cell differentiation and disease progression in TAK. METHODS: Ninety-five patients with TAK, 26 patients with small vessel vasculitis, and 40 healthy donors were enrolled. Naive and memory CD4+ T cells were activated with anti-CD3/CD28 beads and analyzed for lineage differentiation. The mTORC1 activity was determined by quantifying intracellular phospho-S6 kinase 1 and phospho-S6 ribosomal protein. Rapamycin and lentiviral regulatory-associated protein of mTOR short hairpin RNA were used to block mTORC1 activity. Human artery-NSG mouse chimeras representing human TAK were established for targeting mTORC1 in disease treatment. RESULTS: TAK CD4+ T cells were selectively prepositioned with hyperactivity of mTORC1 (P < 0.001), resulting in spontaneous maldifferentiation of Th1 and Th17 cells (P < 0.001). Activity of mTORC1high in circulating CD4+ T cells predicted elevated frequencies of proinflammatory T cells and active disease in TAK patients (P < 0.001). Blockade of mTORC1 with rapamycin efficiently abrogated the maldifferentiation of Th1 and Th17 cells (P < 0.01) and ameliorated vasculitis in humanized TAK chimeras (P < 0.001). Inhibition of mTORC1 using RNA interference technology is sufficient to reduce proinflammatory T cell frequencies (P < 0.01) and restrict TAK disease progression in vivo (P < 0.01). CONCLUSION: Our findings indicate that hyperactivity of mTORC1 is a critical cell-intrinsic mechanism underlying spontaneous maldifferentiation of proinflammatory T cells in TAK patients. Targeting mTORC1 is a promising therapeutic strategy against TAK.
OBJECTIVE: Takayasu arteritis (TAK) is a progressive autoimmune large vessel vasculitis with infiltration of proinflammatory T cells, with a largely unknown etiology. This study was undertaken to explore the involvement of mechanistic target of rapamycin (mTOR) in proinflammatory T cell differentiation and disease progression in TAK. METHODS: Ninety-five patients with TAK, 26 patients with small vessel vasculitis, and 40 healthy donors were enrolled. Naive and memory CD4+ T cells were activated with anti-CD3/CD28 beads and analyzed for lineage differentiation. The mTORC1 activity was determined by quantifying intracellular phospho-S6 kinase 1 and phospho-S6 ribosomal protein. Rapamycin and lentiviral regulatory-associated protein of mTOR short hairpin RNA were used to block mTORC1 activity. Human artery-NSG mouse chimeras representing human TAK were established for targeting mTORC1 in disease treatment. RESULTS: TAK CD4+ T cells were selectively prepositioned with hyperactivity of mTORC1 (P < 0.001), resulting in spontaneous maldifferentiation of Th1 and Th17 cells (P < 0.001). Activity of mTORC1high in circulating CD4+ T cells predicted elevated frequencies of proinflammatory T cells and active disease in TAK patients (P < 0.001). Blockade of mTORC1 with rapamycin efficiently abrogated the maldifferentiation of Th1 and Th17 cells (P < 0.01) and ameliorated vasculitis in humanized TAK chimeras (P < 0.001). Inhibition of mTORC1 using RNA interference technology is sufficient to reduce proinflammatory T cell frequencies (P < 0.01) and restrict TAK disease progression in vivo (P < 0.01). CONCLUSION: Our findings indicate that hyperactivity of mTORC1 is a critical cell-intrinsic mechanism underlying spontaneous maldifferentiation of proinflammatory T cells in TAK patients. Targeting mTORC1 is a promising therapeutic strategy against TAK.