SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity.
SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity.
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DOI：
10.1186/s12974-022-02594-9
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发表时间：
2022-10-03
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
多发性硬化症（MS）是一种以中枢神经系统自身免疫为特征的慢性衰弱疾病，其病因复杂，涉及环境和遗传因素。我们目前对多发性硬化症的理解指出免疫系统失调是致病的罪魁祸首，然而，许多与多发性硬化症易感性增加相关的基因是如何参与的仍然未知。其中一个与多发性硬化症易感性相关并已知调节免疫功能的基因是自体配体免疫细胞受体SLAMF7。我们将WT和SLAMF7 - / -小鼠置于多种EAE模型中，比较疾病严重程度，并全面描述这些小鼠的中枢神经系统免疫景观。我们鉴定了所有表达slamf7的CNS免疫细胞，并比较了基因型之间的整个CNS免疫生态位。我们通过光谱细胞术和BioPlex检测对B细胞和T细胞进行了深入的表型和体外功能研究。还进行了将WT和SLAMF7−/−B细胞转移到B细胞缺陷小鼠（μMT）的过继转移研究。最后，我们进行了B-T细胞共培养研究，并构建了基于SLAMF7+和SLAMF7−人脑脊液免疫细胞scRNA-seq数据的细胞-细胞相互作用网络。我们发现，与WT小鼠相比，SLAMF7−/−小鼠对EAE更敏感，并且发现SLAMF7在许多CNS免疫细胞亚群上表达。SLAMF7的缺失并未严重改变CNS免疫景观，但在EAE期间以模型依赖的方式改变了免疫细胞亚群浸润。全球缺乏SLAMF7表达增加骨髓细胞激活状态，同时增强T细胞抗mog免疫。B细胞谱研究显示，在EAE期间，SLAMF7 - / -小鼠的特定血浆和B细胞亚群的激活状态增加，功能共培养研究确定SLAMF7 - / - B细胞诱导过度的T细胞激活。过继性转移研究表明，SLAMF7- / -小鼠对EAE的易感性增加部分依赖于B细胞，人类脑脊液SLAMF7相互作用组的重建发现B细胞对表达SLAMF7的细胞之间的细胞间通信至关重要。我们的研究发现了SLAMF7在中枢神经系统免疫调节和B细胞功能中的新作用，并阐明了SLAMF7与ms之间遗传关联的基础。
Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit, however, it remains unknown as to how the many genes associated with increased susceptibility to MS are involved. One such gene linked to MS susceptibility and known to regulate immune function is the self-ligand immune cell receptor SLAMF7. We subjected WT and SLAMF7−/− mice to multiple EAE models, compared disease severity, and comprehensively profiled the CNS immune landscape of these mice. We identified all SLAMF7-expressing CNS immune cells and compared the entire CNS immune niche between genotypes. We performed deep phenotyping and in vitro functional studies of B and T cells via spectral cytometry and BioPlex assays. Adoptive transfer studies involving the transfer of WT and SLAMF7−/− B cells into B cell-deficient mice (μMT) were also performed. Finally, B–T cell co-culture studies were performed, and a comparative cell–cell interaction network derived from scRNA-seq data of SLAMF7+ vs. SLAMF7− human CSF immune cells was constructed. We found SLAMF7−/− mice to be more susceptible to EAE compared to WT mice and found SLAMF7 to be expressed on numerous CNS immune cell subsets. Absence of SLAMF7 did not grossly alter the CNS immune landscape, but allowed for altered immune cell subset infiltration during EAE in a model-dependent manner. Global lack of SLAMF7 expression increased myeloid cell activation states along with augmented T cell anti-MOG immunity. B cell profiling studies revealed increased activation states of specific plasma and B cell subsets in SLAMF7−/− mice during EAE, and functional co-culture studies determined that SLAMF7−/− B cells induce exaggerated T cell activation. Adoptive transfer studies revealed that the increased susceptibility of SLAMF7−/− mice to EAE is partly B cell dependent and reconstruction of the human CSF SLAMF7-interactome found B cells to be critical to cell–cell communication between SLAMF7-expressing cells. Our studies have identified novel roles for SLAMF7 in CNS immune regulation and B cell function, and illuminate underpinnings of the genetic association between SLAMF7 and MS. The online version contains supplementary material available at 10.1186/s12974-022-02594-9.
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影响因子：
4.4
作者：
Aldhamen, Yasser Ali;Seregin, Sergey S.;Amalfitano, Andrea
通讯作者：
Amalfitano, Andrea
DOI：
10.4049/jimmunol.1401805
发表时间：
2014-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chaudhry MS;Karadimitris A
通讯作者：
Karadimitris A
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
4.6
作者：
Boyden, Alexander W.;Brate, Ashley A.;Karandikar, Nitin J.
通讯作者：
Karandikar, Nitin J.
影响因子：
5.2
作者：
Ban, Maria;Liao, Wenjia;Sawcer, Stephen
通讯作者：
Sawcer, Stephen