Gut-licensed β7+ CD4+ T cells contribute to progressive retinal ganglion cell damage in glaucoma
Gut-licensed β7+ CD4+ T cells contribute to progressive retinal ganglion cell damage in glaucoma
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DOI：
10.1126/scitranslmed.adg1656
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发表时间：
2023-08-02
影响因子：
17.1
通讯作者：
Lu, Fang
中科院分区：
文献类型：
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作者：
He, Chong;Xiu, Wenbo;Lu, Fang
青光眼是导致不可逆失明的主要原因。目前，大多数治疗策略旨在降低升高的眼内压（EIOP），但这并不总是阻止疾病进展。有证据表明T细胞在青光眼发病机制中的作用，但其潜在机制在很大程度上仍然未知。在此，我们发现青光眼患者循环中表达肠道归巢整合素β 7的CD 4（+）T细胞百分比增加，并且与疾病分期相关。在EIOP触发的青光眼小鼠模型中，在青光眼进行期，β 7（+）CD 4（+）T细胞通过诱导视网膜内皮细胞表达粘膜血管地址素细胞粘附分子1（MAdCAM-1）浸润视网膜。MAdCAM-1在健康小鼠的视网膜中最低限度地检测到，并且用MAdCAM-1抗体中和可改善青光眼小鼠的视网膜神经节细胞（RGC）损失和神经胶质活性。我们进一步发现，EIOP诱导的β 7（+）CD 4（+）T细胞在青光眼急性期归巢到肠道，这对患病小鼠进行性RGC损伤至关重要。肠道归巢β 7（+）CD 4（+）T细胞经历转录重编程，显示在自身免疫性疾病、细菌反应、粘膜免疫和神经胶质活性中富集的上调途径。Guthoming β 7（+）CD 4（+）T细胞获得了诱导视网膜MAdCAM-1表达和穿过血-视网膜屏障的能力。总之，我们的研究揭示了肠道许可的β 7（+）CD 4（+）T细胞和MAdCAM-1在RGC变性中的作用，并强调了“肠道-视网膜”轴在青光眼中的重要性。
Glaucoma is the leading cause of irreversible blindness. Currently, most therapeutic strategies aim to reduce elevated intraocular pressure (EIOP), but this does not always halt disease progression. Evidence suggests a role for T cells in glaucoma pathogenesis, but the underlying mechanisms remain largely unknown. Here, we found that the percentage of circulating CD4(+) T cells expressing a gut-homing integrin beta 7 was increased in patients with glaucoma and was associated with disease stage. In an EIOP-triggered glaucoma mouse model, beta 7(+) CD4(+) T cells infiltrated the retina in the progressive phase of glaucoma via eliciting retinal endothelial cell expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). MAdCAM-1 was minimally detected in retinas of healthy mice, and neutralization with an MAdCAM-1 antibody ameliorated retinal ganglion cell (RGC) loss and glial activity in mice with glaucoma. We furthermore found that EIOP-induced beta 7(+) CD4(+) T cells homed to the gut during the acute phase of glaucoma, which was essential for progressive RGC damage in diseased mice. Gut-homing beta 7(+) CD4(+) T cells underwent transcriptional reprogramming, showing up-regulated pathways enriched in autoimmune diseases, bacteria responses, mucosal immunity, and glial activity. Guthoming beta 7(+) CD4(+) T cells gained the competence to induce retinal MAdCAM-1 expression and to cross the blood-retina barrier. Together, our study reveals a role of gut- licensed beta 7(+) CD4(+) T cells and MAdCAM-1 in RGC degeneration and emphasizes the importance of the "gut-retina" axis in glaucoma.