Abstract
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.
Acknowledgements
We thank Prof. Ian Ganley, University of Dundee, UK, for allowing us to access Mito-QC mice under a Material Transfer Agreement. Genotyped mice were provided by Dr. Martin Young’s laboratory at UAB. Mice were maintained and utilized for in vivo experiments according to the MTA guidelines. We gratefully acknowledge Dr. Regan Moore, Oxford Nano Imaging, for collaborations for nanoimaging experiments with both human and MDRC-derived sEVs and for analyses of all nanoimaging data. We gratefully acknowledge Marion Spell at the UAB Flow Cytometry Core Facilities, Shawn Williams and Robert Grabski at the High Resolution Imaging Facility, James Kizziah at the Cryo-EM Core Facility, and Sagar Hanumanthu at the Shelby Comprehensive Flow Cytometry Core Facility for technical assistance in sEVs flow cytometry, confocal microscopy, and ImageStream flow cytometry, respectively.
Funding
This work was supported by FAMRI YCSA 2010, Parker B. Francis Fellowship and R01HL128502 awarded to J.S.D., U54 ES030246-01 awarded to M.A., R01 HL173154 awarded to V.J.T., HT9425-24-1-0304 and HL139617awarded to J.Z., Nathan Shock Center P30 G050886 (J.Z. and V.D.U.), the Swedish Heart-Lung Foundation Grant # 20200646, 20230528 (S.G.), The Swedish Research Council 2022-01170 (S.G.), NIH P30 AR048311 and NIH P30 AI27667 for service and support provided by the UAB Comprehensive Flow Cytometry Core, NIH grant P30 CA013148 and additional funding from NIH grant S10 OD024978 for service and support provided by the UAB Cryo-EM Facility under the Institutional Research Core Program and O’Neal Comprehensive Cancer Center.
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S.G. holds a patent on B-cell-derived exosomes in immune therapy. J.S.D and K.F.G. are equal partners within Dynamic Tissue Mimics LLC, the work presented in this manuscript is independent of this interest. There is currently no financial interest associated with this interest or role. All other authors declare no competing interests.
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Hough, K.P., Trevor, J.L., Ahmad, S. et al. Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73684-y
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DOI: https://doi.org/10.1038/s41467-026-73684-y
