Skin-Resident Effector Memory CD8(+)CD28(-) T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.
Skin-Resident Effector Memory CD8(+)CD28(-) T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.
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DOI：
10.1016/j.jid.2016.11.037
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Fuschiotti P
中科院分区：
文献类型：
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作者：
Li G;Larregina AT;Domsic RT;Stolz DB;Medsger TA Jr;Lafyatis R;Fuschiotti P
CD8+ T 细胞的 CD28 表达会随着年龄的增长和慢性炎症而丧失。 CD8+CD28− T 细胞是异质细胞亚群，其功能范围从免疫抑制到效应。在这里，我们分析了 CD8+CD28− T 细胞在系统性硬化症 (SSc) 发病机制中的作用，系统性硬化症是一种以自身免疫、血管病变和广泛皮肤和内脏纤维化为特征的结缔组织疾病。我们发现，SSc 患者血液和受影响皮肤中 CD8+CD28− T 细胞的频率增加，与患者年龄无关，并且与皮肤纤维化程度相关。我们发现大多数亲皮肤CD8+CD28−T细胞在疾病早期存在于患者的皮损中，表现出效应记忆表型并表现出强烈的离体细胞溶解活性。皮肤驻留和循环 SSc CD8+CD28− T 细胞产生高水平的促纤维化细胞因子 IL-13，诱导正常和 SSc 真皮成纤维细胞产生胶原蛋白。因此，我们的研究结果表明，CD8+CD28− T 细胞代表了 SSc 中的致病性 T 细胞亚群，并且可能在 SSc 皮肤病的早期阶段发挥着关键作用。
Loss of CD28 expression by CD8+ T cells occurs with age and during chronic inflammatory conditions. CD8+CD28− T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8+CD28− T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8+CD28− T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that the majority of skin-tropic CD8+CD28− T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8+CD28− T cells produce high levels of the pro-fibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8+CD28− T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease.