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

Immune aging manifests with a combination of failing adaptive immunity and insufficiently restrained inflammation. In patients with rheumatoid arthritis (RA), T cell aging occurs prematurely, but the mechanisms involved and their contribution to tissue-destructive inflammation remain unclear. We found that RA CD4+ T cells showed signs of aging during their primary immune responses and differentiated into tissue-invasive, pro-inflammatory effector cells. RA T cells had low expression of the double-strand-break repair nuclease MRE11A, leading to telomeric damage, juxtacentromeric heterochromatin unraveling, and senescence marker upregulation. Inhibition of MRE11A activity in healthy T cells induced the aging phenotype, whereas MRE11A overexpression in RA T cells reversed it. In human-synovium chimeric mice, MRE11Alow T cells were tissue-invasive and pro-arthritogenic, and MRE11A reconstitution mitigated synovitis. Our findings link premature T cell aging and tissue-invasiveness to telomere deprotection and heterochromatin unpacking, identifying MRE11A as a therapeutic target to combat immune aging and suppress dysregulated tissue inflammation.

Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed “circulating DNA-containing ICs”), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.

This article reports that TLR9 signaling can reduce intrinsic microRNA-7 (miR-7) expression in human lung cancer cells and that overexpression of miR-7 can significantly inhibit TLR9 signaling–enhanced growth and metastatic potential of lung cancer cells in vitro and in vivo.