Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells

Yi Shen, Zhenke Wen, Yinyin Li, Eric Lawrence Matteson, Jison Hong, Jörg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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. ATPlo pyruvatelo 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.

Original languageEnglish (US)
Pages (from-to)1025-1034
Number of pages10
JournalNature Immunology
Volume18
Issue number9
DOIs
StatePublished - Aug 22 2017

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ASJC Scopus subject areas

  • Immunology

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