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<p>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<sup>+</sup> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • 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

摘要

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.