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A pathologically expanded, clonal lineage of IL-21–producing CD4+ T cells drives inflammatory neuropathy
Maryamsadat Seyedsadr, … , Melissa G. Lechner, Maureen A. Su
Maryamsadat Seyedsadr, … , Melissa G. Lechner, Maureen A. Su
Published August 1, 2024
Citation Information: J Clin Invest. 2024;134(15):e178602. https://doi.org/10.1172/JCI178602.
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Research Article Autoimmunity Immunology

A pathologically expanded, clonal lineage of IL-21–producing CD4+ T cells drives inflammatory neuropathy

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Abstract

Inflammatory neuropathies, which include chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain Barré syndrome (GBS), result from autoimmune destruction of the PNS and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we used paired single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor–sequencing (scTCR-Seq) of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21–expressing CD4+ T cells that were clonally expanded and multifunctional. These IL-21–expressing CD4+ T cells consisted of 2 transcriptionally distinct expanded cell populations, which expressed genes associated with T follicular helper (Tfh) and T peripheral helper (Tph) cell subsets. Remarkably, TCR clonotypes were shared between these 2 IL-21–expressing cell populations, suggesting a common lineage differentiation pathway. Finally, we demonstrated that IL-21 receptor–KO (IL-21R–KO) mice were protected from neuropathy development and had decreased immune infiltration into peripheral nerves. IL-21 signaling upregulated CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.

Authors

Maryamsadat Seyedsadr, Madison F. Bang, Ethan C. McCarthy, Shirley Zhang, Ho-Chung Chen, Mahnia Mohebbi, Willy Hugo, Jason K. Whitmire, Melissa G. Lechner, Maureen A. Su

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Figure 4

IL-21R signaling is required for neuropathy development in NOD.AireGW/ mice.

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IL-21R signaling is required for neuropathy development in NOD.AireGW/ m...
(A) Neuropathy-free incidence curve for female NOD.AireGW/ IL-21RKO versus NOD.AireGW/ IL-21RHet versus NOD.AireGW/ IL-21RWT mice. **P < 0.01, by Mantel-Cox test. (B and C) Representative distal and proximal compound muscle action potentials from IL-21R–sufficient versus IL-21R–deficient NOD.AireGW/ sciatic nerves. The latency, duration, amplitude, and NCV were quantified and compared between groups (n = 6). **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired 2-tailed t test. (D and E) Immune cell infiltration scores in the forelimb nerves as assessed by H&E staining and compared between groups (n = 6). ****P < 0.0001, by unpaired 2-tailed t test. Scale bar: 200 μm. (F) The frequency and number of CD4+ T cells, B lymphocytes (CD4–CD8–B220+), and CD8+ T cells were compared between groups in the peripheral nerves (n = 6). *P < 0.05 and **P < 0.01, by 2-way ANOVA with Bonferroni’s multiple correction.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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