Pro-Inflammatory c-Met⁺ CD4 T Cells in Multiple Sclerosis.

IF 7.7 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2025-09-26 DOI:10.1002/ana.78035

Gautier Breville, Mahdia Benkhoucha, Ayman Rezk, Ngoc Lan Tran, Isis Senoner, Amit Bar-Or, Patrice H Lalive

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引用次数: 0

Abstract

Objective: Hepatocyte growth factor (HGF) binds exclusively the c-Met surface receptor, and the HGF/c-Met axis regulates T cell function in autoimmune diseases. We analyzed c-Met expression on human CD4 T cells in the blood and cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) versus non-inflammatory neurological disease (NIND), to better understand the role of CD4 T cells in MS.

Methods: We recruited 34 untreated MS patients (age 28-44 years) and 13 NIND (age 34-51 years) who underwent paired blood and CSF sampling at the time of diagnosis work-up. Phenotypic and functional CD4 T cells characterization was determined by flow cytometry and bulk RNA sequencing. Adhesion and transmigration capacities were studied to further characterize the function of c-Met⁺ CD4 T cells.

Results: c-Met⁺ memory CD4 T cells were detected at higher levels in both blood (median of 1.98%) and CSF (5.88%) in MS compared to NIND (0.37% and 0.68%, respectively) (p < 0.0001). Ex vivo c-Met⁺ CD4 T cells exhibited higher levels of GM-CSF, interleukin (IL)-17, interferon (IFN)- $γ$ , and double positive IL-17⁺IFN- $γ$ ⁺ expression, compared with c-Met^- CD4 T cells. c-Met⁺ CD4 T cells expressed increased levels of integrins-Itgα4β1 (VLA-4) and ItgαLβ2 (LFA-1)-compared with c-Met^- CD4 T cells. Anti-Itgα4 (natalizumab) and anti-ItgαLβ2 (odulimomab) inhibited CD4 T cell transmigration with predominant inhibition of CD4 T cells expressing c-Met.

Interpretation: These results emphasize c-Met as an immune marker of highly pro-inflammatory and migratory CD4 T lymphocytes in both the periphery and central nervous system of MS patients. ANN NEUROL 2025.

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促炎性c-Met+ CD4 T细胞在多发性硬化中的作用。

目的：肝细胞生长因子（HGF）单独结合c-Met表面受体，HGF/c-Met轴调节自身免疫性疾病中的T细胞功能。我们分析了多发性硬化症（MS）和非炎症性神经疾病（NIND）患者血液和脑脊液（CSF）中c-Met在人CD4 T细胞上的表达，以更好地了解CD4 T细胞在MS中的作用。方法：我们招募了34名未经治疗的MS患者（28-44岁）和13名NIND患者（34-51岁），他们在诊断时接受了配对血液和脑脊液采样。通过流式细胞术和大量RNA测序确定CD4 T细胞的表型和功能特征。我们研究了c-Met+ CD4 T细胞的粘附和迁移能力，以进一步表征其功能。结果：c-Met+记忆性CD4 T细胞在两种血液中检测到较高水平（中位数为1.98）%) and CSF (5.88%) in MS compared to NIND (0.37% and 0.68%, respectively) (p + CD4 T cells exhibited higher levels of GM-CSF, interleukin (IL)-17, interferon (IFN)- γ $$ \upgamma $$ , and double positive IL-17+IFN- γ $$ \gamma $$ + expression, compared with c-Met- CD4 T cells. c-Met+ CD4 T cells expressed increased levels of integrins-Itgα4β1 (VLA-4) and ItgαLβ2 (LFA-1)-compared with c-Met- CD4 T cells. Anti-Itgα4 (natalizumab) and anti-ItgαLβ2 (odulimomab) inhibited CD4 T cell transmigration with predominant inhibition of CD4 T cells expressing c-Met.Interpretation: These results emphasize c-Met as an immune marker of highly pro-inflammatory and migratory CD4 T lymphocytes in both the periphery and central nervous system of MS patients. ANN NEUROL 2025.

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.