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Objective <p>Non-canonical myeloid cell populations are increasingly recognized as critical regulators of inflammation in neuroimmunological disease. Here, we investigate the role of alternatively activated neutrophils (aaN) in limiting encephalitogenic T cell responses during experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis.</p> Methods <p>Arginase-1–expressing aaN were identified and characterized within central nervous system (CNS) infiltrates during EAE using flow cytometry, single-cell RNA sequencing, and fluorescent in situ hybridization (RNAscope) combined with immunohistochemistry. The immunomodulatory properties of aaN were evaluated in vitro using CD4⁺ T cell suppression assays and in vivo by adoptive transfer of ex vivo–generated aaN during the preclinical phase following encephalitogenic T-cell injection.</p> Results <p>aaN were consistently detected within the CNS throughout EAE and spatially co-localized with encephalitogenic T cells. Transcriptomic profiling of aaN revealed enrichment of pathways associated with regulation of T cell activation and immune suppression. CNS-derived aaN potently inhibited CD4⁺ T cell proliferation in vitro. Therapeutic augmentation of this population, via adoptive transfer of ex vivo–generated aaN into mice following the injection of encephalitogenic T cells, delayed clinical EAE onset, markedly reduced the accumulation of pathogenic T cells within CNS lesions, and significantly enhanced neuronal survival. Mechanistically, ex vivo–generated aaN suppressed T cell responses through a contact-dependent, PD-L1–independent pathway, indicating a previously unrecognized mode of neutrophil-mediated immunoregulation.</p> Interpretation <p>These findings identify aaN as a previously underappreciated immunoregulatory population within the inflamed CNS that restrains pathogenic T cell responses and limits neuroinflammation during EAE. Collectively, our data support the therapeutic potential of strategies that augment aaN activity, including autologous aaN-based cell therapy or interventions that promote CNS homing, polarization, and persistence of endogenous aaN, as novel approaches for disease modification in multiple sclerosis.</p>

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Alternatively activated neutrophils limit T cell–driven neuroinflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Jeffrey R. Atkinson,
  • Calli Bellinger,
  • Andrew D. Jerome,
  • Ashley Munie Gardner,
  • Hayley K. Groover,
  • Shuo Chen,
  • Arnetta McVey Moffatt,
  • Jesse A. Sepeda,
  • Amy Dokiburra,
  • Luke A. Hammond,
  • Tom Liu,
  • Amy Webb,
  • Andrew R. Sas,
  • Benjamin M. Segal

摘要

Objective

Non-canonical myeloid cell populations are increasingly recognized as critical regulators of inflammation in neuroimmunological disease. Here, we investigate the role of alternatively activated neutrophils (aaN) in limiting encephalitogenic T cell responses during experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis.

Methods

Arginase-1–expressing aaN were identified and characterized within central nervous system (CNS) infiltrates during EAE using flow cytometry, single-cell RNA sequencing, and fluorescent in situ hybridization (RNAscope) combined with immunohistochemistry. The immunomodulatory properties of aaN were evaluated in vitro using CD4⁺ T cell suppression assays and in vivo by adoptive transfer of ex vivo–generated aaN during the preclinical phase following encephalitogenic T-cell injection.

Results

aaN were consistently detected within the CNS throughout EAE and spatially co-localized with encephalitogenic T cells. Transcriptomic profiling of aaN revealed enrichment of pathways associated with regulation of T cell activation and immune suppression. CNS-derived aaN potently inhibited CD4⁺ T cell proliferation in vitro. Therapeutic augmentation of this population, via adoptive transfer of ex vivo–generated aaN into mice following the injection of encephalitogenic T cells, delayed clinical EAE onset, markedly reduced the accumulation of pathogenic T cells within CNS lesions, and significantly enhanced neuronal survival. Mechanistically, ex vivo–generated aaN suppressed T cell responses through a contact-dependent, PD-L1–independent pathway, indicating a previously unrecognized mode of neutrophil-mediated immunoregulation.

Interpretation

These findings identify aaN as a previously underappreciated immunoregulatory population within the inflamed CNS that restrains pathogenic T cell responses and limits neuroinflammation during EAE. Collectively, our data support the therapeutic potential of strategies that augment aaN activity, including autologous aaN-based cell therapy or interventions that promote CNS homing, polarization, and persistence of endogenous aaN, as novel approaches for disease modification in multiple sclerosis.