Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London School of Medicine, London, UK.
Clin Exp Immunol. 2013 Oct;174(1):18-26. doi: 10.1111/cei.12161.
Balanced immunoregulatory networks are essential for maintenance of systemic tolerance. Disturbances in the homeostatic equilibrium between inflammatory mediators, immune regulators and immune effector cells are implicated directly in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). In this study we characterize the peripheral blood CD8(+) CD28(-) regulatory T cells (Treg) contribution to the immunoregulatory network in health and in RA. In health, CD8(+) CD28(-) Treg are suppressive but, unlike CD4(+) Treg , they function predominantly through the action of soluble mediators such as interleukin (IL)-10 and transforming growth factor (TGF)-β. Neutralization of TGF-β consistently reduced CD8(+) CD28(-) Treg suppressor function in vitro. RA, CD8(+) CD28(-) Treg are increased numerically, but have reduced expression of inducible co-stimulator (ICOS) and programmed death 1 (PD-1) compared to healthy or disease controls. They produce more IL-10 but autologous T cells express less IL-10R. This expression was found to be restored following in-vitro addition of a tumour necrosis factor inhibitor (TNFi). Deficiencies in both the CD8(+) CD28(-) Treg population and reduced sensitivity of the T responder cells impact upon their regulatory function in RA. TNFi therapy partially restores CD8(+) CD28(-) Treg ability in vivo and in vitro, despite the defects in expression of functionally relevant molecules by RA CD8(+) CD28(-) Treg compared to healthy controls. This study places CD8(+) CD28(-) Treg cells in the scheme of immune regulation alongside CD4(+) Treg cells, and highlights the importance of understanding impaired responsiveness to regulation that is common to these suppressor subsets and their restored function in response to TNFi therapy.
平衡的免疫调节网络对于维持全身耐受至关重要。炎症介质、免疫调节剂和免疫效应细胞之间的内稳态平衡失调直接涉及包括类风湿关节炎（RA）在内的自身免疫性疾病的发病机制。在这项研究中，我们描述了外周血 CD8(+) CD28(-) 调节性 T 细胞（Treg）对健康和 RA 中免疫调节网络的贡献。在健康状态下，CD8(+) CD28(-) Treg 具有抑制作用，但与 CD4(+) Treg 不同，它们主要通过可溶性介质如白细胞介素（IL）-10 和转化生长因子（TGF）-β的作用发挥功能。TGF-β的中和作用一致降低了 CD8(+) CD28(-) Treg 的体外抑制功能。与健康或疾病对照相比，RA 中 CD8(+) CD28(-) Treg 的数量增加，但诱导共刺激分子（ICOS）和程序性死亡受体 1（PD-1）的表达减少。它们产生更多的 IL-10，但自身 T 细胞表达的 IL-10R 较少。这种表达在体外添加肿瘤坏死因子抑制剂（TNFi）后得到恢复。CD8(+) CD28(-) Treg 群体的缺陷和 T 反应细胞敏感性的降低都影响了它们在 RA 中的调节功能。尽管与健康对照相比，RA CD8(+) CD28(-) Treg 表达功能相关分子的缺陷，但 TNFi 治疗部分恢复了 CD8(+) CD28(-) Treg 在体内和体外的功能。这项研究将 CD8(+) CD28(-) Treg 细胞置于与 CD4(+) Treg 细胞一起的免疫调节方案中，并强调了理解这些抑制性亚群普遍存在的对调节的反应受损以及它们对 TNFi 治疗的恢复功能的重要性。
