Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma
12 affiliations
- 1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
- 2Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
- 3Department of Histology, Medical University of Gdansk, Gdansk, Poland
- 4Division of Global and Rural Health, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA
- 5Department of Cellular Biology & Anatomy, LSUHS, LSU Health, Shreveport, LA, USA
- 6Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
- 7Department of Biology, Ashoka University, National Capital Region-Delhi, India
- 8Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
- 9Department of Medicine, Tulane University School of Medicine and the Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA
- 10Clinical Immunology and Transfusion Medicine and Center for Molecular Medicine, The Karolinska University Hospital, Stockholm, Sweden
- 11Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- 12Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. [email protected]
Abstract
Small extracellular vesicles (sEVs) are known to orchestrate cell-cell communication, but the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown. Myeloid-derived regulatory cells (MDRCs) are known to 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; these cells are drivers of chronic airway inflammation in asthma. CD4+ T cells internalize sEVs containing mitochondria predominantly by membrane fusion, and blocking mitochondrial oxidant signaling in MDRC-derived sEVs mitigates T cell activation. Reactive oxygen species-mediated signaling that elicits T cell activation in asthmatics is sEV-dependent. Additionally, a Drp1-dependent mechanism in pro-inflammatory MDRCs promotes mitochondrial packaging within sEVs, which then co-localize with the polarized cytoskeleton and mitochondrial networks in recipient T cells. Importantly, intranasal transfer of mitochondria packaged sEVs enhances airway inflammation and Th polarization in vivo in a murine model of asthma. Thus, our studies indicate a previously unrecognized role for mitochondrial fission and sEV-mediated mitochondrial transfer-mediated signaling in dysregulated T cell activation and Th cell polarization in asthma which could constitute a novel therapeutic target.
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BibTeX
@article{hough2026small,
title = {{Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma}},
author = {Kenneth P. Hough and Jennifer L. Trevor and Shaheer Ahmad and Yong Wang and Balu K. Chacko and Kayla F. Goliwas and John G. Strenkowski and Yuelong Liu and Joanna I. Nowak and Eugene Becker and Young-il Kim and Renita Holmes and Nathaniel B. Bone and Shia Vang and A Hassan D I Pritchard and Jay Chin and Sandeep Bodduluri and Veena B. Antony and Sultan Tousif and Mohammad Athar and Diptiman Chanda and Kasturi Mitra and Jaroslaw W. Zmijewski and Jianhua Zhang and Steven R. Duncan and Victor John Thannickal and Susanne Gabrielsson and Victor M. Darley-Usmar and Jessy S. Deshane},
journal = {Nature Communications},
year = {2026},
month = may,
doi = {10.1038/s41467-026-73684-y},
url = {https://doi.org/10.1038/s41467-026-73684-y},
note = {CC BY},
}
RIS
TY - JOUR
TI - Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma
AU - Kenneth P. Hough
AU - Jennifer L. Trevor
AU - Shaheer Ahmad
AU - Yong Wang
AU - Balu K. Chacko
AU - Kayla F. Goliwas
AU - John G. Strenkowski
AU - Yuelong Liu
AU - Joanna I. Nowak
AU - Eugene Becker
AU - Young-il Kim
AU - Renita Holmes
AU - Nathaniel B. Bone
AU - Shia Vang
AU - A Hassan D I Pritchard
AU - Jay Chin
AU - Sandeep Bodduluri
AU - Veena B. Antony
AU - Sultan Tousif
AU - Mohammad Athar
AU - Diptiman Chanda
AU - Kasturi Mitra
AU - Jaroslaw W. Zmijewski
AU - Jianhua Zhang
AU - Steven R. Duncan
AU - Victor John Thannickal
AU - Susanne Gabrielsson
AU - Victor M. Darley-Usmar
AU - Jessy S. Deshane
PY - 2026
DA - 2026/05/26
JO - Nature Communications
DO - 10.1038/s41467-026-73684-y
UR - https://doi.org/10.1038/s41467-026-73684-y
AB - Small extracellular vesicles (sEVs) are known to orchestrate cell-cell communication, but the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown. Myeloid-derived regulatory cells (MDRCs) are known to 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; these cells are drivers of chronic airway inflammation in asthma. CD4+ T cells internalize sEVs containing mitochondria predominantly by membrane fusion, and blocking mitochondrial oxidant signaling in MDRC-derived sEVs mitigates T cell activation. Reactive oxygen species-mediated signaling that elicits T cell activation in asthmatics is sEV-dependent. Additionally, a Drp1-dependent mechanism in pro-inflammatory MDRCs promotes mitochondrial packaging within sEVs, which then co-localize with the polarized cytoskeleton and mitochondrial networks in recipient T cells. Importantly, intranasal transfer of mitochondria packaged sEVs enhances airway inflammation and Th polarization in vivo in a murine model of asthma. Thus, our studies indicate a previously unrecognized role for mitochondrial fission and sEV-mediated mitochondrial transfer-mediated signaling in dysregulated T cell activation and Th cell polarization in asthma which could constitute a novel therapeutic target.
SN - 2041-1723
ER -