期刊
NATURE IMMUNOLOGY
卷 18, 期 9, 页码 1025-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3808
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资金
- US National Institutes of Health [R01 AR042527, R01 HL 117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779, U19 AI057266, I01 BX001669]
Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATP(lo)pyruvate(lo) conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.
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