A macrophage-mediated TNFa signaling axis within peripheral nerves is required for initiation of autoimmune peripheral neuropathy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE180498 | GEO | 2021/11/30
REPOSITORIES: GEO
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Project description:CIDP (chronic inflammatory demyelinating polyneuropathy) is a debilitating immune-mediated neuropathy characterized by progressive weakness and sensory loss. Peripheral nerves from affected patients and mouse models show infiltrating CD4+ T cells, and CD4+ T cells from affected mice are sufficient to transfer neuropathy to immunodeficient recipients, suggesting an important role for CD4+ T cells in disease pathogenesis. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we report that IL-21 expression is highly expressed and a unique feature of terminally-differentiated effector CD4+ T cells within peripheral nerves of neuropathic mice. IL-21-expressing CD4+ T cells are comprised of two transcriptionally distinct, clonally expanded populations, which express genes associated with Tfh and Tph subsets. Remarkably, TCR clonotypes were shared between these two IL-21-expressing populations, suggesting lineage differentiation from a common progenitor. Finally, we demonstrate that IL-21 signaling is required for pathogenic T cell infiltration into peripheral nerves through upregulation of CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings highlight IL-21 signaling, Tfh and Tph differentiation, and CXCR6-mediated cellular localization as key pathogenic pathways and potential therapeutic targets in inflammatory neuropathies.
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