CD8+ T cells recognizing a neuron-restricted antigen injure axons in a model of multiple sclerosis.
CD8+ T cells recognizing a neuron-restricted antigen injure axons in a model of multiple sclerosis.
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DOI：
10.1172/jci162788
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发表时间：
2023-11-01
影响因子：
15.9
通讯作者：
Howe, Charles L.
中科院分区：
文献类型：
--
作者：
Clarkson, Benjamin D. S.;Grund, Ethan M.;Standiford, Miranda M.;Mirchia, Kanish;Westphal, Maria S.;Muschler, Liz S.;Howe, Charles L.
在与疾病进展相关的多发性硬化（MS）病变中，CD 8 + T细胞数量超过CD 4+细胞，但这些克隆扩增效应物的致病作用和抗原靶点尚不清楚。基于脱髓鞘是MS疾病进展所必需但不充分的证据，我们以前假设CNS浸润的CD 8 + T细胞对神经元抗原具有特异性，直接驱动轴突和神经元损伤，导致MS患者的累积性神经功能障碍。我们现在发现脱髓鞘诱导神经元和轴突上MHC I类的表达，并导致神经元特异性新抗原的呈递在一个实施方案中，将鸡卵清蛋白（突触蛋白启动子驱动的鸡卵清蛋白）与抗原特异性CD 8 + T细胞（抗卵清蛋白OT-I TCR转基因T细胞）结合。这些神经抗原特异性效应物在没有脱髓鞘的情况下监视CNS，但没有保留。然而，在通过铜腙中毒诱导脱髓鞘后，神经抗原特异性CD 8 + T细胞增殖，在CNS中积累，并损伤表达新抗原的神经元和轴突。我们进一步报告了MS患者组织中灰质和白色物质束中MHC I类和β2-微球蛋白转录物和蛋白的神经元表达升高。这些发现支持自身反应性抗轴突和抗神经元CD 8 + T细胞在MS进展中的致病作用。
CD8+ T cells outnumber CD4+ cells in multiple sclerosis (MS) lesions associated with disease progression, but the pathogenic role and antigenic targets of these clonally expanded effectors are unknown. Based on evidence that demyelination is necessary but not sufficient for disease progression in MS, we previously hypothesized that CNS-infiltrating CD8+ T cells specific for neuronal antigens directly drive the axonal and neuronal injury that leads to cumulative neurologic disability in patients with MS. We now show that demyelination induced expression of MHC class I on neurons and axons and resulted in presentation of a neuron-specific neoantigen (synapsin promoter–driven chicken ovalbumin) to antigen-specific CD8+ T cells (anti-ovalbumin OT-I TCR-transgenic T cells). These neuroantigen-specific effectors surveilled the CNS in the absence of demyelination but were not retained. However, upon induction of demyelination via cuprizone intoxication, neuroantigen-specific CD8+ T cells proliferated, accumulated in the CNS, and damaged neoantigen-expressing neurons and axons. We further report elevated neuronal expression of MHC class I and β2-microglobulin transcripts and protein in gray matter and white matter tracts in tissue from patients with MS. These findings support a pathogenic role for autoreactive anti-axonal and anti-neuronal CD8+ T cells in MS progression.
小鼠脊髓浸润CD8+淋巴细胞的功能表征。
影响因子：
3.3
作者：
Deb C;Howe CL
通讯作者：
Howe CL
影响因子：
3.7
作者：
Deb C;Lafrance-Corey RG;Schmalstieg WF;Sauer BM;Wang H;German CL;Windebank AJ;Rodriguez M;Howe CL
通讯作者：
Howe CL