Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Department of Clinical Immunology, The Third Affiliate Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China.
Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China.
Mol Ther. 2019 Nov 6;27(11):1963-1973. doi: 10.1016/j.ymthe.2019.07.014. Epub 2019 Jul 26.
Many patients with systemic lupus erythematosus (SLE) have lupus nephritis, one of the severe complications of SLE. We previously reported that CD8+CD103+ T regulatory cells induced ex vivo with transforming growth factor β (TGF-β) (iTregs) inhibited immune cells responses to ameliorate excessive autoimmune inflammation. However, the molecular mechanism(s) underlying the role of these CD8+ iTregs is still unclear. Here we identified that CD39, which is highly expressed on CD8+ iTregs, crucially contributes to the immunosuppressive role of the CD8+CD103+ iTregs. We showed that adoptive transfer of CD8+CD103+ iTregs significantly relieves the chronic graft-versus-host disease with lupus nephritis and CD39 inhibitor mostly abolished the functional activities of these CD8+ iTregs in vitro and in vivo. CD39+ cells sorted from CD8+CD103+ iTregs were more effective in treating lupus nephritis than CD39- partner cells in vivo. Furthermore, human CD8+ iTregs displayed increased CD103 and CD39 expressions, and CD39 was involved in the suppressive function of human CD8+ iTregs. Thus, our data implicated a crucial role of CD39 in CD8+CD103+ iTregs in treating lupus nephritis, and CD39 could be a new phenotypic biomarker for the identification of highly qualified CD8+ Tregs. This subpopulation may have therapeutic potential in patients with SLE nephritis and other autoimmune diseases.
许多系统性红斑狼疮 (SLE) 患者患有狼疮肾炎，这是 SLE 的严重并发症之一。我们之前报道过，用转化生长因子β (TGF-β) 体外诱导的 CD8+CD103+T 调节细胞 (iTregs) 抑制免疫细胞的反应，从而改善过度的自身免疫炎症。然而，这些 CD8+iTregs 作用的分子机制尚不清楚。在这里，我们发现 CD39 在 CD8+iTregs 上高度表达，对 CD8+CD103+iTregs 的免疫抑制作用至关重要。我们表明，CD8+CD103+iTregs 的过继转移显著缓解了狼疮肾炎慢性移植物抗宿主病，而 CD39 抑制剂在体外和体内基本上消除了这些 CD8+iTregs 的功能活性。与 CD39- 配对细胞相比，从 CD8+CD103+iTregs 中分选的 CD39+细胞在体内更有效地治疗狼疮肾炎。此外，人 CD8+iTregs 显示出增加的 CD103 和 CD39 表达，并且 CD39 参与了人 CD8+iTregs 的抑制功能。因此，我们的数据表明 CD39 在 CD8+CD103+iTregs 治疗狼疮肾炎中起着关键作用，CD39 可以作为鉴定高活性 CD8+Tregs 的新表型生物标志物。该亚群可能在 SLE 肾炎和其他自身免疫性疾病患者中具有治疗潜力。
