Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma
- Kenneth P. Hough
- Jennifer L. Trevor
- Shaheer Ahmad
- Yong Wang
- Balu K. Chacko
- Kayla F. Goliwas
- John G. Strenkowski
- Yuelong Liu
- Joanna I. Nowak
- Eugene J. Becker Jr
- Young-Il Kim
- Renita Holmes
- Nathaniel B. Bone
- Shia Vang
- Alexandra Pritchard
- Jay Chin
- Sandeep Bodduluri
- Veena B. Antony
- Sultan Tousif
- Mohammad Athar
- Diptiman Chanda
- Kasturi Mitra
- Jaroslaw W. Zmijewski
- Jianhua Zhang
- Steven R. Duncan
- Victor J. Thannickal
- Susanne Gabrielsson
- Victor M. Darley-Usmar
- Jessy S. Deshane
2026-05-26
Small extracellular vesicles (sEVs) orchestrate cell-cell communication, but the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown. Myeloid-derived regulatory cells (MDRCs) control CD4 + T cell responses in asthma. We demonstrate that airway MDRC-derived sEVs from asthmatics mediate T cell receptor engagement and transfer of mitochondria that induce antigen-specific activation and polarization of Th17 and Th2 cells. sEV-dependent T cell activation and Th polarization were mediated by mitochondrial oxidant-dependent NF-κB signaling, which, when blocked, mitigated CD4 + T cell activation. Mitochondrial fission regulator, DRP-1, promoted mitochondrial packaging within MDRC-sEVs. Internalized sEVs co-localized with the polarized cytoskeleton and mitochondrial networks in recipient T cells. Intranasal transfer of mitochondria packaged sEVs enhanced allergic airway inflammation and Th polarization in a murine asthma model. Our studies indicate a previously unrecognized role for mitochondrial fission and sEV- mitochondria-mediated signaling in dysregulated T cell activation, Th polarization, and pathology in asthma.