Translational Research Program at the Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
Sci Transl Med. 2013 Jan 30;5(170):170ra15. doi: 10.1126/scitranslmed.3004970.
Patients with multiple sclerosis (MS) manifest demyelination and neurodegeneration mediated in part by CD4(+) T cells that have escaped regulation. Resistance of pathogenic effector T cells (T(effs)) to suppression by regulatory T cells (T(regs)) has been demonstrated in several autoimmune diseases. Although impairment in T(reg) number and function has been observed in relapsing-remitting MS (RRMS), T(eff) resistance has not been well studied in this disease. To determine whether T(eff) resistance contributes to failed tolerance in RRMS, we performed T(reg) suppression assays with T(effs) from either RRMS patients not on immunomodulatory therapy or healthy individuals. T(eff) resistance was present in the T(effs) of RRMS patients with active disease but not from patients with inactive disease. Interleukin-6 (IL-6) and phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) promote T(eff) resistance to T(regs), and we found an increase in IL-6 receptor α (IL-6Rα) expression and elevated IL-6 signaling as measured by pSTAT3 in our RRMS subjects. Further, the impaired suppression in RRMS subjects correlated with an increase in IL-6Rα surface expression on CD4(+) T cells and an increase in pSTAT3 in response to IL-6. To address whether the enhanced pSTAT3 contributed to T(eff) resistance in active RRMS patients, we blocked STAT3 phosphorylation and found that impaired suppression was reversed. Therefore, enhanced IL-6R signaling through pSTAT3, in some cases through increased IL-6Rα expression, contributed to T(eff) resistance in active RRMS. These markers may aid in determining disease activity and responsiveness to immunomodulatory therapies in RRMS.
多发性硬化症 (MS) 患者表现出脱髓鞘和神经退行性变，部分由逃脱调节的 CD4(+) T 细胞介导。在几种自身免疫性疾病中已经证明了致病性效应 T 细胞 (T(effs)) 对调节性 T 细胞 (T(regs)) 抑制的抵抗。尽管在复发缓解型多发性硬化症 (RRMS) 中观察到 T(reg) 数量和功能受损，但在该疾病中尚未很好地研究 T(eff) 抵抗。为了确定 T(eff) 抵抗是否导致 RRMS 中耐受失败，我们对来自未接受免疫调节治疗的 RRMS 患者或健康个体的 T(effs) 进行了 T(reg) 抑制测定。在活跃疾病的 RRMS 患者的 T(effs) 中存在 T(eff) 抵抗，但在不活跃疾病的患者中不存在。白细胞介素 6 (IL-6) 和信号转导和转录激活因子 3 (pSTAT3) 的磷酸化促进 T(eff) 抵抗 T(regs)，我们发现我们的 RRMS 受试者中 IL-6 受体 α (IL-6Rα) 表达增加和 IL-6 信号升高，如 pSTAT3 测量所示。此外，RRMS 受试者中抑制作用受损与 CD4(+) T 细胞上的 IL-6Rα 表面表达增加和对 IL-6 的 pSTAT3 增加相关。为了解决增强的 pSTAT3 是否导致活跃 RRMS 患者的 T(eff) 抵抗，我们阻断了 STAT3 磷酸化，发现抑制作用受损得到逆转。因此，通过 pSTAT3 增强的 IL-6R 信号传导，在某些情况下通过增加 IL-6Rα 表达，导致活跃 RRMS 中的 T(eff) 抵抗。这些标志物可能有助于确定 RRMS 中的疾病活动和对免疫调节疗法的反应性。
