Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Computational and Systems Immunology Program, Stanford University School of Medicine, Stanford, California, USA.
Ann Clin Transl Neurol. 2021 Jan;8(1):163-176. doi: 10.1002/acn3.51264. Epub 2021 Jan 5.
To characterize T-cell receptors (TCRs) and identify target epitopes in multiple sclerosis (MS).
Peripheral blood mononuclear cells were obtained from 39 MS patients and 19 healthy controls (HCs). TCR repertoires for α/β/δ/γ chains, TCR diversity, and V/J usage were determined by next-generation sequencing. TCR β chain repertoires were compared with affectation status using a novel clustering method, Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH). Cytomegalovirus (CMV)-IgG was measured in an additional 113 MS patients and 93 HCs. Regulatory T cells (Tregs) were measured by flow cytometry.
TCR diversity for all four chains decreased with age. TCRα and TCRβ diversity was higher in MS patients (P = 0.0015 and 0.024, respectively), even after age correction. TRAJ56 and TRBV4-3 were more prevalent in MS patients than in HCs (p = 0.027 and 0.040, respectively). GLIPH consolidated 208,674 TCR clones from MS patients into 1,294 clusters, among which two candidate clusters were identified. The TRBV4-3 cluster was shared by HLA-DRB104:05-positive patients (87.5%) and predicted to recognize CMV peptides (CMV-TCR). MS Severity Score (MSSS) was lower in patients with CMV-TCR than in those without (P = 0.037). CMV-IgG-positivity was associated with lower MSSS in HLA-DRB104:05 carriers (P = 0.0053). HLA-DRB104:05-positive individuals demonstrated higher CMV-IgG titers than HLA-DRB104:05-negative individuals (P = 0.017). CMV-IgG-positive patients had more Tregs than CMV-IgG-negative patients (P = 0.054).
High TCRα/TCRβ diversity, regardless of age, is characteristic of MS. Association of a CMV-recognizing TCR with mild disability indicates CMV's protective role in HLA-DRB1*04:05-positive MS.
鉴定多发性硬化症（MS）中的 T 细胞受体（TCR）并确定其靶抗原表位。
从 39 名 MS 患者和 19 名健康对照者（HC）中获取外周血单核细胞。采用下一代测序技术检测 TCRα/β/δ/γ 链的 TCR 库、多样性和 V/J 使用情况。采用新型聚类方法（通过变区热点对淋巴细胞相互作用的分组，GLIPH）将 TCRβ 库与受累情况进行比较。在另外 113 名 MS 患者和 93 名 HC 中检测巨细胞病毒（CMV）-IgG。采用流式细胞术检测调节性 T 细胞（Treg）。
所有 4 条链的 TCR 多样性均随年龄增长而降低。MS 患者的 TCRα 和 TCRβ 多样性更高（分别为 P=0.0015 和 0.024），即使校正年龄后也是如此。TRAJ56 和 TRBV4-3 在 MS 患者中比 HC 更常见（p=0.027 和 0.040）。GLIPH 将来自 MS 患者的 208674 个 TCR 克隆整合为 1294 个簇，其中鉴定出两个候选簇。TRBV4-3 簇在 HLA-DRB104:05 阳性患者中共享（87.5%），并预测可识别 CMV 肽（CMV-TCR）。MS 严重程度评分（MSSS）在有 CMV-TCR 的患者中低于无 CMV-TCR 的患者（P=0.037）。在 HLA-DRB104:05 携带者中，CMV-IgG 阳性与较低的 MSSS 相关（P=0.0053）。与 HLA-DRB104:05 阴性者相比，HLA-DRB104:05 阳性者的 CMV-IgG 滴度更高（P=0.017）。CMV-IgG 阳性患者的 Treg 多于 CMV-IgG 阴性患者（P=0.054）。
无论年龄大小，MS 的 TCRα/TCRβ 多样性较高是其特征。与轻度残疾相关的 CMV 识别 TCR 表明 CMV 在 HLA-DRB1*04:05 阳性 MS 中具有保护作用。
