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Inflammatory neuropathy driven by a pathologically expanded, clonal lineage of IL-21 producing CD4+ T cells [scRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE252646 | GEO | 2024/01/23

REPOSITORIES: GEO

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Inflammatory neuropathy driven by a pathologically expanded, clonal lineage of IL-21 producing CD4+ T cells [TCR-seq]

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.

2024-01-23 | GSE252647 | GEO

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus

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2024-07-08 | GSE233050 | GEO

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cell in lupus [Time_coure_RNAseq]

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2024-09-22 | GSE277730 | GEO

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus [JUN IFN]

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2024-07-08 | GSE252917 | GEO

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus [JUN OE]

2024-07-08 | GSE233048 | GEO

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus [JUN AHR modulation]

2024-07-08 | GSE233047 | GEO

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus [AHR]

Project description:SLE is prototypical autoimmune disease driven by pathologic T cell-B cell interactions. Expansion of B cell-helper T cells including T follicular helper (Tfh) and T peripheral helper (Tph) cells is a prominent feature of systemic lupus erythematosus (SLE). Human Tfh and Tph cells characteristically produce high levels of the B cell chemoattractant CXCL135,6, yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4 T cell phenotypes in SLE patients, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4 T cells. Transcriptomic, epigenetic, and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ Tph/Tfh cell differentiation and promote an IL-22+ phenotype. Type I interferon (IFN), a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ Tph/Tfh cells on a polarization axis opposite from Th22 cells and reveal AHR, JUN, and IFN as key regulators of these divergent T cell states.

2024-07-08 | GSE233045 | GEO

Peripheral blood T helper cells circulate with pathogenic tissue resident T helper cells in chronic GVHD

Project description:Chronic graft versus host disease (cGVHD) is a systemic autoimmune-like syndrome. The role of Tph cells in the pathogenesis of cGVHD has not been examined, although previous studies have shown that cGVHD is characterized by loss of Tfh cells. Here, we show that in cGVHD patients and in a murine model that reflects characteristic features of human cGVHD, the proportions of Tph cells among CD4+ T cells in the blood were expanded. These cells augmented memory B cell differentiation and production of IgG via IL-21. Adoptive transfer experiments showed recirculation between Tph in the blood and tissue-resident T helper (Trh) cells in GVHD target tissues. The TCR repertoires of blood Tph cells and Trh cells in GVHD target tissues of mice were highly overlapping.

2023-02-22 | GSE200520 | GEO

Interleukin 21 drives CXCR6+ CD8+ T cell mediators in Autoimmune Checkpoint Inhibitor Thyroiditis

Project description:Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. To delineate human IRAE pathogenesis, we sampled thyroid tissue from subjects with ICI-thyroiditis and HT. Using single cell RNA sequencing of human thyroid fine needle aspiration (FNA) specimens, we identify CXCR6+ interferon gamma (IFN)+ cytotoxic CD8+ T cells as key contributors to ICI-thyroiditis (IRAE). This is in contrast to the primary role for CD4+ Th17 cells in the pathogenesis of HT (14, 15). Interestingly, we also found a supporting role for IL21-producing CD4+ T follicular (Tfh) and peripheral helper (Tph) cells via the upregulation of CXCR6 and cytotoxic function in CD8+ T cells.

2023-05-17 | GSE218743 | GEO

Expression Data from in vivo Tfh vs GC Tfh vs non-Tfh

Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. Analysis of in vivo polyclonal GC Tfh vs Tfh vs Non-Tfh eight days after LCMV viral infection. Analysis of in vivo follicular helper CD4 T cells (CXCR5high GL7low), versus germinal center follicular helper CD4 T cells (CXCR5hi GL7hi), versus non-follicular helper CD4 T cells (CXCR5low) eight days after viral infection.

2010-04-28 | E-GEOD-21380 | biostudies-arrayexpress

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