Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 1, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI136042
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Funding
- NIH [R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, P01 HL129941, R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191]
- Govenar Discovery Fund
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The dysfunction of CD8(+) regulatory T cells in autoimmune vasculitis is attributed to aberrant NOTCH4 signaling, leading to limited vesicular secretion of the enzyme NADPH oxidase 2 (NOX2) and subsequent breakdown of tissue tolerance, resulting in aggressive vessel wall inflammation.
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(+) Treg cells fail to contain CD4(+) T cells and macrophages, resulting in the formation of tissue-destructive granulomatous lesions. Here, we report that the molecular defect of malfunctioning CD8(+) 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(hi)CD8(+) Treg cells increased RABSA and RAB11A expression and suppressed RAB7A, culminating in the accumulation of early and recycling endosomes and sequestering of NOX2 in an intracellular compartment. RAB7A(lo)DD8(+) Treg cells failed in the surface translocation and exosomal release of NOX2. NOTCH4(hi)RAB5A(hi)RAB7A(lo)RAB11A(hi)CD8(+) 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.
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