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5 recordsLinked to original sources
PubMed2026

Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.

Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic aggregate-prone proteins, which are characteristic pathological hallmarks of neurodegenerative diseases. As we previously found that microglia secreted factors impair neuronal autophagy and identified CCL3, CCL4 and CCL5 as causative chemokines, we screened the microglial secretome for soluble factors and neuronal cytokine receptors to identify candidates impacting autophagy in neuronal models. Against our expectations of identifying negative regulators, we found that two receptor-ligand pairs, CXCR3-CXCL10 and CXCR5-CXCL13, stimulated autophagy across several neuronal models, both in vitro (SH-SY5Y, i3Neurons) and in vivo. Mechanistically, CXCL10 and CXCL13 promoted autophagy through a shared mechanism: cognate receptor stimulation led to downstream activation of JNK, which in turn phosphorylates BCL-XL, promoting its disassociation from BECN1. The freed BECN1 interacts with VPS34 to form the autophagy initiation complex, enhancing autophagosome formation and flux. These findings reveal chemokine signalling as a targetable pathway for neuronal autophagy induction in neurodegeneration.

Journal Article↗
PubMed2025

High-Dimensional Immunophenotyping of Post-COVID-19 and Post-Influenza Patients Reveals Persistent and Specific Immune Signatures After Acute Respiratory Infection.

Long-term consequences of SARS-CoV-2 infection are unknown since recovered individuals can experience symptoms and latent viral reactivation for months. Indeed, acute post-infection sequelae have also been observed in other respiratory viral infections, including influenza. To characterize post-COVID-19 and post-influenza induced alterations to the cellular immunome, peripheral blood mononuclear cells (PBMCs) were obtained from patients 3 months after recovery from COVID-19 (n = 93) or influenza (n = 25), and from pre-pandemic healthy controls (n = 25). PBMCs were characterized using a 40-plex mass cytometry panel. Principal component analysis (PCA), classification models, and K-means clustering were subsequently applied. PCA identified distinct immune profiles between cohorts, with both post-COVID and post-flu patients displaying an altered chemokine receptor expression compared to pre-pandemic healthy controls. These alterations were more prominent in post-COVID patients since they exhibited highly increased expression of chemokine receptors CXCR3 and CCR6 by various lymphoid populations, while post-influenza patients mainly showed a decrease in CCR4 expression by naïve T cells, monocytes, and conventional dendritic cells. Classification models using immunophenotyping data confirm the three groups, while K-means clustering revealed two subgroups among post-COVID patients, with younger patients showing more pronounced immune alterations in the chemokine receptor profile, independently of long COVID symptoms. In conclusion, post-COVID and post-influenza patients exhibit distinct and unique persistent immune alterations. Understanding these altered immune profiles can guide targeted therapies for post-COVID syndrome and highlight differences in immune recovery from various respiratory infections.

Humans↗
PubMed2025

DNA methylation and multi-omics profiling of T cells uncovers chemotactic pathways and proliferation-linked hypomethylation in narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a loss of orexin-producing cells in the brain and involves autoimmune mechanisms, including the presence of autoreactive T cells. In this study, we performed genome-wide DNA methylation analysis using both CD4+/CD8+ T cells from 42 NT1 patients and 42 controls across discovery and replication cohorts. To identify methylation changes more robustly associated with the disease, we prioritized differentially methylated regions (DMRs) over single-site differentially methylated positions (DMPs). Furthermore, to validate and interpret DMP-level associations, we integrated genome-wide genotype and gene expression data obtained from the same individuals. As a result, the DMR analysis identified 15 reproducible DMRs in CD4+ T cells and 5 in CD8+ T cells, with most DMRs shared between the two cell types. Shared DMRs included regions associated with CCL5 (p = 2.1E-02) and CCR4 (p = 8.3E-03). Integrative analysis with genotype and gene expression data also showed that the DMP related to S100A4, which promotes lymphocyte migration through CCR5 and CXCR3 receptors, was associated with the disease in CD4+ T cells. Pathway analysis of genes identified through both the DMR and integrative analyses indicated enrichment in cell chemotaxis-related pathways, suggesting that aberrant chemokine-mediated cell migration plays a central role in NT1 pathogenesis. Further, NT1-associated methylation changes were predominantly hypomethylation events, significantly enriched in non-promoter, non-CpG island regions (p = 1.74E-102). We further observed that global hypomethylation levels were correlated with hypoSC, a mitotic index estimated from methylation data, highlighting increased T cell proliferation in NT1.

Humans↗
PubMed2025

Refined cell transfer model reveals roles for Ascl2 and Cxcr3 in splenic localization of mouse NK cells during virus infection.

Cell transfer experiments complement the rigorous investigation of antiviral and antitumor functions of natural killer (NK) cells. Success in these endeavors is enhanced by expansion of small numbers of input NK cells driven by viral antigens or homeostatic proliferation in immunodeficient hosts. In contrast, analysis of other NK-cell functions, including immunoregulation, are non-proliferative and require an intact immune system in recipient mice. We reveal poor persistence of conventional congenic (CD45.1) BoyJ NK cells following adoptive transfer in comparison to CRISPR-generated CD45.1+ (JAXBoy) NK cells. Reciprocal transfers between C57BL/6 and JAXBoy mice substantially improve seeding and maintenance of donor NK cells. Using this system, we confirm that CXCR3 re-positions NK cells in the white pulp of the spleen after infection, which is vital for immunoregulation. Moreover, we discovered that the transcription factor ASCL2 is required for recruitment of NK cells into the spleen and white pulp. These results provide improved tools and novel insights into NK cell biology.

Animals↗
PubMed2026

Eltrombopag-associated remodeling of the MAIT, MR1+ and γδ T cells in pediatric immune thrombocytopenia.

Pediatric immune thrombocytopenia (ITP) is an autoimmune cytopenia characterized by immune-mediated platelet destruction and impaired thrombopoiesis. Mucosa-associated invariant T (MAIT) cells are innate-like T cells activated by MR1-presented microbial metabolites and inflammatory cytokines, but their role in pediatric ITP and their relationship to eltrombopag therapy remain unclear. We analyzed peripheral blood mononuclear cells from healthy controls (n = 20), untreated pediatric ITP patients (n = 60), and eltrombopag-treated patients (n = 16). MAIT cells were quantified using MR1-5-OP-RU tetramers and surrogate gating (CD3+Vα7.2+CD161+). MAIT subsets, memory phenotype, chemokine receptor expression (CXCR3, CXCR5, CCR6), HLA-DR, intracellular cytokines (IFN-γ, TNF-α, IL-17 A, IL-22), and MR1+CD3- cells were analyzed by flow cytometry. Tetramer-defined MAIT cells were reduced in absolute number in pediatric ITP, including eltrombopag-treated patients, most prominently within the CD8+ subset, whereas their frequency among CD3+ T cells did not differ between untreated and eltrombopag-treated groups. In contrast, CD3+Vα7.2+CD161+ cells increased in untreated ITP and were lower in eltrombopag-treated patients. Untreated ITP patients exhibited reduced frequencies of IFN-γ- and TNF-α-producing MAIT cells, accompanied by increased IL-17-producing cells and TNF-α signal intensity. Conventional αβ T cells were reduced, whereas γδ T cells were increased; eltrombopag-treated patients exhibited γδ T-cell frequencies and cytokine-positive fractions closer to those of healthy controls. MR1+CD3- cells were expanded and displayed reduced HLA-DR expression in untreated ITP, whereas eltrombopag-treated patients showed lower MR1+CD3- frequencies and HLA-DR levels closer to healthy controls. These findings demonstrate coordinated alterations of the MAIT/MR1 axis and unconventional T-cell compartments in pediatric ITP and identify immunophenotypic differences associated with eltrombopag treatment.

Humans↗