Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma

Area of Science:

• Immunology
• Cell Biology
• Respiratory Medicine

Background:

• Small extracellular vesicles (sEVs) mediate intercellular communication.
• Myeloid-derived regulatory cells (MDRCs) influence T cell responses in asthma.
• The role of sEVs and mitochondria in asthmatic airway inflammation is not well understood.

Purpose of the Study:

• To investigate the role of MDRC-derived sEVs and their mitochondria in asthmatic airway inflammation.
• To elucidate the mechanisms of sEV-mediated T cell activation and polarization in asthma.
• To explore the potential of targeting sEV-mitochondria signaling for asthma therapy.

Main Methods:

• Characterization of MDRC-derived sEVs from asthmatic patients.
• Analysis of mitochondrial transfer from sEVs to T cells.
• Assessment of T cell activation, polarization (Th17, Th2), and NF-κB signaling.
• Inhibition of mitochondrial fission regulator DRP-1 and NF-κB signaling.
• Murine asthma model to evaluate the in vivo effects of sEVs.

Main Results:

• Asthmatic MDRC-derived sEVs transfer mitochondria to CD4+ T cells, inducing antigen-specific activation and Th17/Th2 polarization.
• sEV-mediated T cell activation and Th polarization depend on mitochondrial oxidant-driven NF-κB signaling.
• DRP-1 promotes mitochondrial packaging into MDRC-sEVs.
• Internalized sEVs integrate into recipient T cell cytoskeleton and mitochondrial networks.
• Intranasal transfer of sEVs with mitochondria exacerbates allergic airway inflammation and Th polarization in mice.

Conclusions:

• MDRC-derived sEVs transmit functional mitochondria to T cells, driving asthmatic airway inflammation.
• Mitochondrial fission and sEV-mitochondria signaling represent a novel mechanism in asthma pathogenesis.
• Targeting sEV-mitochondria interactions may offer a therapeutic strategy for asthma.