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The aorta and the large conductive arteries are immunoprivileged tissues and are protected against inflammatory attack. A breakdown of immunoprivilege leads to autoimmune vasculitis, such as giant cell arteritis, in which [CD8.sup.+] Treg cells fail to contain [CD4.sup.+] T cells and macrophages, resulting in the formation of tissue-destructive granulomatous lesions. Here, we report that the molecular defect of malfunctioning [CD8.sup.+] Treg cells lies in aberrant NOTCH4 signaling that deviates endosomal trafficking and minimizes exosome production. By transcriptionally controlling the profile of RAB GTPases, NOTCH4 signaling restricted vesicular secretion of the enzyme NADPH oxidase 2 (NOX2). Specifically, [NOTCH4.sup.hi][CD8.sup.+] Treg cells increased RAB5A and RAB11A expression and suppressed RAB7A, culminating in the accumulation of early and recycling endosomes and sequestering of NOX2 in an intracellular compartment. [RAB7A.sup.lo][CD8.sup.+] Treg cells failed in the surface translocation and exosomal release of NOX2. [NOTCH4.sup.hi][RAB5A.sup.hi][RAB7A.sup.lo][RAB11A.sup.hi][CD8.sup.+] Treg cells left adaptive immunity unopposed, enabling a breakdown in tissue tolerance and aggressive vessel wall inflammation. Inhibiting NOTCH4 signaling corrected the defect and protected arteries from inflammatory insult. This study implicates NOTCH4-dependent transcriptional control of RAB proteins and intracellular vesicle trafficking in autoimmune disease and in vascular inflammation., Introduction The aorta and its major side branches are nonredundant for host survival and are protected against inflammatory attack; an immune privilege broken in the case of vasculitis (1). In [...]

While previous studies have identified cancer stem‐like cells (CSCs) as a crucial driver for chemoresistance and tumor recurrence, the underlying mechanisms for populating the CSC pool remain unclear. Here, we identify hypermitophagy as a feature of human lung CSCs, promoting metabolic adaption via the Notch1‐AMPK axis to drive CSC expansion. Specifically, mitophagy is highly active in CSCs, resulting in increased mitochondrial DNA (mtDNA) content in the lysosome. Lysosomal mtDNA acts as an endogenous ligand for Toll‐like receptor 9 (TLR9) that promotes Notch1 activity. Notch1 interacts with AMPK to drive lysosomal AMPK activation by inducing metabolic stress and LKB1 phosphorylation. This TLR9‐Notch1‐AMPK axis supports mitochondrial metabolism to fuel CSC expansion. In patient‐derived xenograft chimeras, targeting mitophagy and TLR9‐dependent Notch1‐AMPK pathway restricts tumor growth and CSC expansion. Taken together, mitochondrial hemostasis is interlinked with innate immune sensing and Notch1‐AMPK activity to increase the CSC pool of human lung cancer. Synopsis: Lung cancer stem‐like cells show high levels of mitophagy, resulting in lysosomal mtDNA accumulation that activates TLR9 and Notch1‐AMPK signaling. The TLR9‐Notch1‐AMPK pathway promotes CSC expansion and can be therapeutically targeted. CSCs show mitophagic hyperactivity, resulting in the accumulation of mtDNA in lysosomes.Lysosomal mtDNA activates TLR9 and drives the expansion of lung CSCs.TLR9 interacts with Notch1, triggering Notch1 activation and subsequent AMPK phosphorylation.Blocking the TLR9‐dependent Notch1‐AMPK pathway inhibits tumor outgrowth and reduces lung CSCs. [ABSTRACT FROM AUTHOR]

Immune aging results in progressive loss of both protective immunity and T cell-mediated suppression, thereby conferring susceptibility to a combination of immunodeficiency and chronic inflammatory disease. Here, we determined that older individuals fail to generate immunosuppressive [CD8.sup.+][CCR7.sup.+] Tregs, a defect that is even more pronounced in the agerelated vasculitic syndrome giant cell arteritis. In young, healthy individuals, [CD8.sup.+][CCR7.sup.+] Tregs are localized in T cell zones of secondary lymphoid organs, suppress activation and expansion of CD4 T cells by inhibiting the phosphorylation of membrane-proximal signaling molecules, and effectively inhibit proliferative expansion of CD4 T cells in vitro and in vivo. We identified deficiency of NADPH oxidase 2 (NOX2) as the molecular underpinning of CD8 Treg failure in the older individuals and in patients with giant cell arteritis. CD8 Tregs suppress by releasing exosomes that carry preassembled NOX2 membrane clusters and are taken up by CD4 T cells. Overexpression of NOX2 in aged CD8 Tregs promptly restored suppressive function. Together, our data support NOX2 as a critical component of the suppressive machinery of CD8 Tregs and suggest that repairing NOX2 deficiency in these cells may protect older individuals from tissue-destructive inflammatory disease, such as large-vessel vasculitis., Introduction The immune system has evolved to protect the host against pathogens and cancerous cells, while keeping tissue-damaging inflammation at a minimum (1). Tregs serve the imperative role of dampening [...]

Objective: Takayasu arteritis (TAK) is a progressive autoimmune large vessel vasculitis with infiltration of proinflammatory T cells, with a largely unknown etiology. This study was undertaken to explore the involvement of mechanistic target of rapamycin (mTOR) in proinflammatory T cell differentiation and disease progression in TAK. Methods: Ninety‐five patients with TAK, 26 patients with small vessel vasculitis, and 40 healthy donors were enrolled. Naive and memory CD4+ T cells were activated with anti‐CD3/CD28 beads and analyzed for lineage differentiation. The mTORC1 activity was determined by quantifying intracellular phospho–S6 kinase 1 and phospho–S6 ribosomal protein. Rapamycin and lentiviral regulatory‐associated protein of mTOR short hairpin RNA were used to block mTORC1 activity. Human artery–NSG mouse chimeras representing human TAK were established for targeting mTORC1 in disease treatment. Results: TAK CD4+ T cells were selectively prepositioned with hyperactivity of mTORC1 (P < 0.001), resulting in spontaneous maldifferentiation of Th1 and Th17 cells (P < 0.001). Activity of mTORC1high in circulating CD4+ T cells predicted elevated frequencies of proinflammatory T cells and active disease in TAK patients (P < 0.001). Blockade of mTORC1 with rapamycin efficiently abrogated the maldifferentiation of Th1 and Th17 cells (P < 0.01) and ameliorated vasculitis in humanized TAK chimeras (P < 0.001). Inhibition of mTORC1 using RNA interference technology is sufficient to reduce proinflammatory T cell frequencies (P < 0.01) and restrict TAK disease progression in vivo (P < 0.01). Conclusion: Our findings indicate that hyperactivity of mTORC1 is a critical cell‐intrinsic mechanism underlying spontaneous maldifferentiation of proinflammatory T cells in TAK patients. Targeting mTORC1 is a promising therapeutic strategy against TAK. [ABSTRACT FROM AUTHOR]