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Targeting Mechanistic Target of Rapamycin Complex 1 Restricts Proinflammatory T Cell Differentiation and Ameliorates Takayasu Arteritis
Author(s) -
Zhang Jifeng,
Zhao Lei,
Wang Jing,
Cheng Zhihua,
Sun Mengyao,
Zhao Jiayi,
Liu Bin,
Liu Xiyu,
Wen Zhenke,
Li Zhibo
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41084
Subject(s) - proinflammatory cytokine , mtorc1 , t cell , pi3k/akt/mtor pathway , immunology , cancer research , inflammation , medicine , biology , microbiology and biotechnology , immune system , signal transduction
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 CD 4+ T cells were activated with anti‐ CD 3/ CD 28 beads and analyzed for lineage differentiation. The mTORC 1 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 mTORC 1 activity. Human artery– NSG mouse chimeras representing human TAK were established for targeting mTORC 1 in disease treatment. Results TAK CD 4+ T cells were selectively prepositioned with hyperactivity of mTORC 1 ( P < 0.001), resulting in spontaneous maldifferentiation of Th1 and Th17 cells ( P < 0.001). Activity of mTORC 1 high in circulating CD 4+ T cells predicted elevated frequencies of proinflammatory T cells and active disease in TAK patients ( P < 0.001). Blockade of mTORC 1 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 mTORC 1 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 mTORC 1 is a critical cell‐intrinsic mechanism underlying spontaneous maldifferentiation of proinflammatory T cells in TAK patients. Targeting mTORC 1 is a promising therapeutic strategy against TAK.