多发性硬化症相关遗传变异 Gly307Ser 对人 CD8 T 细胞功能的影响。

Impact of the Multiple Sclerosis-Associated Genetic Variant Gly307Ser on Human CD8 T-Cell Functions.

机构信息

From the Infinity-Toulouse Institute for Infectious and Inflammatory Diseases (E.M., V.A., I.B., Y.A., F.M., A.S.D., A.A., A.S.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1291, Centre National de la Recherche Scientifique (CNRS) UMR 5051, Université Paul Sabatier (UPS), Toulouse, France; Institute of Experimental Immunology (E.F., N.N., B.B.), University of Zurich, Switzerland; and Cancer Research Center of Toulouse (CRCT) (L.M.), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier (UPS), Toulouse, France.

出版信息

Neurol Neuroimmunol Neuroinflamm. 2024 Nov;11(6):e200306. doi: 10.1212/NXI.0000000000200306. Epub 2024 Sep 4.

DOI:10.1212/NXI.0000000000200306

PMID:39231385

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11379124/

Abstract

BACKGROUND AND OBJECTIVES

The rs763361 nonsynonymous variant in the gene, which results in a glycine-to-serine substitution at position 307 of the CD226 protein, has been implicated as a risk factor of various immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may play a significant role in predisposing individuals to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the proinflammatory potential of effector CD4 T cells. However, the impact of this CD226 gene variant on CD8 T-cell functions, a population that also plays a key role in MS, remains to be determined.

METHODS

To study whether the CD226 risk variant affects human CD8 T-cell functions, we used CD8 T cells isolated from peripheral blood mononuclear cell of 16 age-matched healthy donors homozygous for either the protective or the risk allele of CD226. We characterized these CD8 T cells on T-cell receptor (TCR) stimulation using high-parametric flow cytometry and bulk RNAseq and through characterization of canonical signaling pathways and cytokine production.

RESULTS

On TCR engagement, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, the transcriptomic signature of CD8 T cells from the donors carrying the risk allele presented an enrichment in TCR, JAK/STAT, and IFNγ signaling. We next found that the CD226-307Ser risk allele leads to a selective increase in the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) associated with enhanced phosphorylation of STAT4 and increased production of IFNγ.

DISCUSSION

Our data suggest that the CD226-307Ser risk variant imposes immune dysregulation by increasing the pathways related to IFNγ signaling in CD8 T cells, thereby contributing to the risk of developing chronic inflammation.

摘要

背景和目的

位于基因上的 rs763361 非同义变体导致 CD226 蛋白第 307 位的甘氨酸被丝氨酸取代，该变体与多种免疫介导的疾病有关，包括多发性硬化症（MS）。强有力的证据表明，该等位基因可能通过降低调节性 T 细胞（Treg）的免疫调节能力和增加效应性 CD4 T 细胞的促炎潜能，在易患 MS 的个体中发挥重要作用。然而，该 CD226 基因变体对 CD8 T 细胞功能的影响，即 MS 中起关键作用的另一类细胞，仍有待确定。

方法

为了研究 CD226 风险变体是否影响人类 CD8 T 细胞功能，我们使用来自外周血单个核细胞的 CD8 T 细胞，这些细胞来自 16 名年龄匹配的健康供体，这些供体均为 CD226 的保护性或风险等位基因纯合子。我们使用高参数流式细胞术和批量 RNAseq 对这些 CD8 T 细胞在 T 细胞受体（TCR）刺激下进行特征描述，并通过特征描述典型的信号通路和细胞因子产生。

结果

在 TCR 结合时，携带保护性（CD226-307Gly）或风险（CD226-307Ser）等位基因的 CD226 的体外 CD8 T 细胞的表型大部分重叠。然而，携带风险等位基因的供体的 CD8 T 细胞的转录组特征表现出 TCR、JAK/STAT 和 IFNγ 信号的富集。接下来，我们发现 CD226-307Ser 风险等位基因导致丝裂原激活蛋白激酶细胞外信号调节激酶 1 和 2（ERK1/2）的磷酸化选择性增加，与 STAT4 的磷酸化增强和 IFNγ 的产生增加相关。