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. ATPlo, pyruvatelo 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.

Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In the autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (TH1) and TH17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating expression of the Notch ligand Jagged1. Vascular endothelial growth factor (VEGF), abundantly present in GCA patients’ blood, induced Jagged1 expression, allowing mvECs to regulate effector T cell induction via the Notch-mTORC1 (mammalian target of rapamycin complex 1) pathway. We found that circulating CD4 T cells in GCA patients have left the quiescent state, actively signal through the Notch pathway and differentiate into TH1 and TH17 effector cells. In an in vivo model of large vessel vasculitis, exogenous VEGF functioned as an effective amplifier to recruit and activate vasculitogenic T cells. Thus, systemic VEGF co-opts endothelial Jagged1 to trigger aberrant Notch signaling, biases responsiveness of CD4 T cells, and induces pathogenic effector functions. Adventitial microvascular networks function as an instructive tissue niche, which can be exploited to target vasculitogenic immunity in large vessel vasculitis.

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N-myristoyltransferase (NMT) attaches the fatty acid myristate to the N-terminal glycine of proteins to sort them into soluble and membrane-bound fractions. Function of the energy-sensing AMP-activated protein kinase (AMPK) is myristoylation-dependent. In rheumatoid arthritis (RA), pathogenic T cells shift glucose away from ATP production towards synthetic and proliferative programs, promoting proliferation, cytokine production, and tissue invasion. We found that RA T cells have a defect in NMT1 function, which prevented AMPK activation and enabled unopposed mTORC1 signaling. Lack of the myristate lipid tail disrupted the lysosomal translocation and activation of AMPK. Instead, myristoylation-incompetent RA T cells hyperactivated the mTORC1 pathway and differentiated into pro-inflammatory T H 1 and T H 17 T helper cells. In vivo, NMT1 loss caused robust synovial tissue inflammation, whereas forced NMT1 overexpression rescued AMPK activation and suppressed synovitis. Thus, NMT1 has tissue-protective functions by facilitating lysosomal recruitment of AMPK and dampening of mTORC1 signaling.

Highlights d The DNA repair nuclease MRE11A is located in mitochondria d Mitochondrial MRE11A protects mtDNA from oxidation and cytoplasmic leakage d MRE11A low T cells fail to produce ATP and undergo caspase-1-dependent pyroptosis d MRE11A loss of function results in tissue inflammation