Department of Medicine, Centre for Rheumatology, University College London, London, UK.
Eur J Immunol. 2010 Feb;40(2):569-78. doi: 10.1002/eji.200939781.
CTLA-4 is a critical gatekeeper of T-cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA-4 in SLE. Our results reveal increased CTLA-4 expression in FOXP3(-) responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA-4 was unable to regulate T-cell proliferation, lipid microdomain formation and phosphorylation of TCR-zeta following CD3/CD28 co-stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co-stimulation, there was no parallel increase in CTLA-4 expression, which would normally provide a break on T-cell proliferation. These defects were associated with exclusion of CTLA-4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA-4 dysfunction as a potential cause for abnormal T-cell activation in patients with SLE, which could be targeted for therapy.
CTLA-4 是 T 细胞活化和免疫耐受的关键调控因子，通过遗传关联与多种自身免疫性疾病有关。由于患有系统性红斑狼疮（SLE）等自身免疫性疾病的患者的 T 细胞表现出特征性的高活性表型，因此我们研究了 CTLA-4 在 SLE 中的功能。我们的研究结果表明，与其他自身免疫性风湿病和健康对照组相比，SLE 患者的 FOXP3(-)反应性 T 细胞中 CTLA-4 的表达增加。然而，与健康 T 细胞不同，CTLA-4 无法调节 T 细胞增殖、TCR-zeta 的脂质微区形成和磷酸化，在 CD3/CD28 共刺激后。尽管狼疮 T 细胞在体外对 CD3/CD28 共刺激有反应，但 CTLA-4 的表达并没有平行增加，这通常会抑制 T 细胞增殖。这些缺陷与 CTLA-4 从脂质微区中排除有关，为其功能丧失提供了一个解剖学基础。总之，我们的数据表明 CTLA-4 功能障碍是 SLE 患者异常 T 细胞活化的潜在原因，这可能成为治疗的靶点。
