Department of Dermatology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
J Immunol. 2011 Mar 15;186(6):3336-45. doi: 10.4049/jimmunol.1001455. Epub 2011 Feb 9.
Human autoimmune diseases are characterized by systemic T cell dysfunction, resulting in chronically activated Th1 and Th17 cells that are inadequately suppressed by regulatory T cells (Tregs). IL-6, which is overexpressed in tissue and serum of patients with autoimmune diseases, inhibits human Treg function. We sought to determine the mechanism for the antitolerogenic properties of IL-6 by examining the signaling pathways downstream of IL-6R in primary human T cells. Inhibition of Stat3 signaling in MLCs containing IL-6 restores Treg-mediated suppression, demonstrating that IL-6-mediated loss of Treg suppression requires phosphorylation of Stat3. Cultures in which either effector T cells (Teffs) or Tregs were pretreated with Stat3 inhibitors indicate that phosphorylated (p)Stat3 is required in both T cell populations for IL-6-mediated reversal of Treg function. IL-21, which signals preferentially through pStat3, also reverses Treg suppression, in contrast to IL-27 and IFN-γ, which signal preferentially through Stat1 and do not inhibit Treg function. Interestingly, both Teffs and Tregs respond to IL-6 stimulation through strong Stat3 phosphorylation with minimal MAPK/Erk activation and moderate Stat1 phosphorylation. Finally, Teffs stimulated strongly through the TCR are also resistant to suppression by Tregs and show concurrent Stat3 phosphorylation. In these cultures, inhibition of pStat3 restores functional suppression by Tregs. Taken together, our findings suggest that an early dominance of Stat3 signaling, prior to subsequent T cell activation, is required for the loss of functional Treg suppression and that kinase-specific inhibitors may hold therapeutic promise in the treatment of autoimmune and chronic inflammatory diseases.
人类自身免疫性疾病的特征是全身 T 细胞功能障碍，导致 Th1 和 Th17 细胞慢性激活，而调节性 T 细胞（Tregs）不能充分抑制这些细胞。在患有自身免疫性疾病的患者的组织和血清中过度表达的白细胞介素 6（IL-6）抑制了人类 Treg 的功能。我们试图通过检查白细胞介素 6 受体（IL-6R）下游的信号通路来确定白细胞介素 6 的不耐受特性的机制。在含有白细胞介素 6 的 MLC 中抑制 Stat3 信号可恢复 Treg 介导的抑制作用，表明白细胞介素 6 介导的 Treg 抑制丧失需要 Stat3 的磷酸化。在效应 T 细胞（Teffs）或 Tregs 预先用 Stat3 抑制剂处理的培养物中表明，磷酸化（p）Stat3 在两种 T 细胞群体中均需要用于白细胞介素 6 介导的 Treg 功能逆转。白细胞介素 21（IL-21）优先通过 pStat3 信号传导，也可逆转 Treg 抑制，而白细胞介素 27（IL-27）和干扰素 γ（IFN-γ）则优先通过 Stat1 信号传导，并且不抑制 Treg 功能。有趣的是，Teffs 和 Tregs 均通过强烈的 Stat3 磷酸化对 IL-6 刺激做出反应，同时 MAPK/Erk 激活最小，Stat1 磷酸化适度。最后，通过 TCR 强烈刺激的 Teffs 也对 Tregs 的抑制具有抗性，并显示出并发的 Stat3 磷酸化。在这些培养物中，抑制 pStat3 可恢复 Tregs 的功能抑制。综上所述，我们的研究结果表明，在随后的 T 细胞激活之前，Stat3 信号的早期优势是 Treg 功能抑制丧失所必需的，并且激酶特异性抑制剂可能在治疗自身免疫和慢性炎症性疾病方面具有治疗潜力。
