严重多发性硬化症患者表现出CD8+调节性T细胞功能改变。

Nail Benallegue, Bryan Nicol, Juliette Lasselin, Severine Bézie, Lea Flippe, Hadrien Regue, Nadege Vimond, Severine Remy, Alexandra Garcia, Fabienne Le Frère, Ignacio Anegon, David Laplaud, Carole Guillonneau
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引用次数: 2

摘要

背景和目的:多发性硬化症(MS)是一种慢性中枢神经系统炎症和脱髓鞘疾病。对MS免疫功能障碍的研究主要集中在CD4+ Tregs上,但CD8+ Tregs的作用仍未被广泛探索。我们之前证实了健康个体的大鼠和人CD8+ cd45rlow /阴性Tregs的抑制特性,表达叉头盒P3 (FOXP3),并通过干扰素-γ (IFN-γ)、转化生长因子β (TGFβ)和白细胞介素-34 (IL-34)起作用。分泌调节免疫反应和控制疾病,如移植排斥反应。为了更好地了解CD8+CD45RClow/阴性Tregs对MS病理的贡献,我们进一步研究了它们在MS患者中的表型、功能和转录组。方法:我们招募了复发-缓解型MS的成人患者和年龄匹配和性别匹配的健康志愿者(HVs)。CD8+ T细胞的分离基于CD45RC的低表达或缺乏表达。首先,根据恶化状态研究CSF和血液中CD8+CD45RClow和阴性的频率,表型,转录组和功能,其次,根据非加重性MS患者的MS严重程度评分(MSSS)的临床严重程度,我们在C57Bl/6小鼠中诱导活性MOG35-55 EAE,并进行新鲜和扩增的CD8+CD45RCneg Tregs过继转移,以评估它们在体内减轻神经炎症的能力。结果:31名未经治疗的复发缓解型MS患者与40名年龄匹配和性别匹配的HVs进行了比较。我们发现脑脊液CD8+CD45RClow和CD8+CD45RCneg比例没有差异,但与HVs相比,MS加重患者血液CD8+CD45RClow频率较低。CD8+CD45RCneg Tregs在体外对MS加重患者的抑制能力高于非急性炎症发作患者。体外功能分析显示,在非加重性重度多发性硬化症患者中,CD8+CD45RClow Tregs的抑制能力受损。然后,我们对小鼠CD8+CD45RCneg Tregs进行了表征,并证明了CD45RCneg细胞在体内迁移到中枢神经系统并减轻实验性自身免疫性脑脊髓炎的潜力。讨论:总之,这些结果提示在MS复发期间CD8+CD45RClow treg的数量和功能缺陷,以及CD8+CD45RClow treg功能障碍与MS严重程度的关联。因此,CD8+ cd45rlow /阴性T细胞可能为MS的病理生理学和新的治疗方法带来新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Patients With Severe Multiple Sclerosis Exhibit Functionally Altered CD8<sup>+</sup> Regulatory T Cells.

Patients With Severe Multiple Sclerosis Exhibit Functionally Altered CD8<sup>+</sup> Regulatory T Cells.

Patients With Severe Multiple Sclerosis Exhibit Functionally Altered CD8<sup>+</sup> Regulatory T Cells.

Patients With Severe Multiple Sclerosis Exhibit Functionally Altered CD8+ Regulatory T Cells.

Background and objectives: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Studies of immune dysfunction in MS have mostly focused on CD4+ Tregs, but the role of CD8+ Tregs remains largely unexplored. We previously evidenced the suppressive properties of rat and human CD8+CD45RClow/neg Tregs from healthy individuals, expressing Forkhead box P3 (FOXP3) and acting through interferon-gamma (IFN-γ), transforming growth factor beta (TGFβ), and interleukin-34 (IL-34). secretions to regulate immune responses and control diseases such as transplant rejection. To better understand CD8+CD45RClow/neg Tregs contribution to MS pathology, we further investigated their phenotype, function, and transcriptome in patients with MS.

Methods: We enrolled adults with relapsing-remitting MS and age-matched and sex-matched healthy volunteers (HVs). CD8+ T cells were segregated based on low or lack of expression of CD45RC. First, the frequency in CSF and blood, phenotype, transcriptome, and function of CD8+CD45RClow and neg were investigated according to exacerbation status and secondarily, according to clinical severity based on the MS severity score (MSSS) in patients with nonexacerbating MS. We then induced active MOG35-55 EAE in C57Bl/6 mice and performed adoptive transfer of fresh and expanded CD8+CD45RCneg Tregs to assess their ability to mitigate neuroinflammation in vivo.

Results: Thirty-one untreated patients with relapsing-remitting MS were compared with 40 age-matched and sex-matched HVs. We demonstrated no difference of CSF CD8+CD45RClow and CD8+CD45RCneg proportions, but blood CD8+CD45RClow frequency was lower in patients with MS exacerbation when compared with that in HVs. CD8+CD45RCneg Tregs but not CD8+CD45RClow showed higher suppressive capacities in vitro in MS patients with exacerbation than in patients without acute inflammatory attack. In vitro functional assays showed a compromised suppression capacity of CD8+CD45RClow Tregs in patients with nonexacerbating severe MS, defined by the MSSS. We then characterized murine CD8+CD45RCneg Tregs and demonstrated the potential of CD45RCneg cells to migrate to the CNS and mitigate experimental autoimmune encephalomyelitis in vivo.

Discussion: Altogether, these results suggest a defect in the number and function of CD8+CD45RClow Tregs during MS relapse and an association of CD8+CD45RClow Tregs dysfunction with MS severity. Thus, CD8+CD45RClow/neg T cells might bring new insights into the pathophysiology and new therapeutic approaches of MS.

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