Li Gang, Larregina Adriana T, Domsic Robyn T, Stolz Donna B, Medsger Thomas A, Lafyatis Robert, Fuschiotti Patrizia
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Invest Dermatol. 2017 May;137(5):1042-1050. doi: 10.1016/j.jid.2016.11.037. Epub 2016 Dec 22.
Loss of CD28 expression by CD8 T cells occurs with age and during chronic inflammatory conditions. CD8CD28 T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8CD28 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 CD8CD28 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 most skin-tropic CD8CD28 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 CD8CD28 T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8CD28 T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease.
CD8⁺ T细胞中CD28表达的丧失会随着年龄增长以及在慢性炎症状态下发生。CD8⁺CD28⁻ T细胞是一个异质性细胞亚群，其功能范围从免疫抑制到效应功能。在此，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、血管病变以及广泛的皮肤和内脏纤维化为特征的结缔组织疾病。我们发现，SSc患者血液和受累皮肤中CD8⁺CD28⁻ T细胞的频率增加，与患者年龄无关，且与皮肤纤维化程度相关。我们发现，大多数归巢至皮肤的CD8⁺CD28⁻ T细胞存在于疾病早期患者的皮肤病变中，表现出效应记忆表型，并在体外具有强大的细胞溶解活性。皮肤驻留和循环的SSc CD8⁺CD28⁻ T细胞产生高水平的促纤维化细胞因子IL-13，其可诱导正常和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细胞是SSc中的致病性T细胞亚群，可能在SSc皮肤病的早期阶段起关键作用。
