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

Pathogenic T cells in rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extra-cellular matrix and form lasting inflammatory microstructures. Here, we found that RA T cells abundantly express the podosome scaffolding protein TKS5, enabling them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells; specifically, reduced glycolytic flux resulting in ATP and pyruvate deficiencies. ATP(lo), pyruvate(lo) conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoring pyruvate production or inhibiting fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their pro-arthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.