Division of Rheumatology, Departments of Medicine, Microbiology and Immunology, and Biochemistry and Molecular Biology, College of Medicine, State University of New York, Upstate Medical University, Syracuse, NY, United States.
Front Immunol. 2021 Mar 2;12:635531. doi: 10.3389/fimmu.2021.635531. eCollection 2021.
Interleukin-2 (IL-2) expands the depleted T regulatory (Treg) cell population, and it has emerged as a potential therapy in systemic lupus erythematosus (SLE). However, IL-2 administration may involve the risk of expanding unwanted pro-inflammatory cells. We herein studied the effects of IL-2 on pro-inflammatory cytokine production by CD4 and CD8 T cells in parallel with Treg development following CD3/CD28 co-stimulation. While Treg cells are depleted in SLE patients, their CD4 T cells were poised to receive and activate IL-2 signaling as evidenced by upregulation of CD25 and enhanced IL-2-incued STAT5 phosphorylation during Treg differentiation. In patients with SLE, however, IL-2 also expanded CD8 T cells capable of producing interleukin-5, interkeukin-13 (IL-13), and interferon-γ (IFN-γ) that occurred with enhanced expression of GATA-3 and phosphorylation of STAT6 but not STAT5. Our data pinpoint a safety signal for systemic administration of IL-2 and challenges a long-held conceptual platform of type 1 and 2 cytokine antagonism by newly documenting the IL-2-dependent development of IL-13 and IFN-γ double-positive (IL-13IFNγ) CD8 T cells in SLE.
白细胞介素-2 (IL-2) 可扩增耗竭的调节性 T 细胞 (Treg) 群，已成为系统性红斑狼疮 (SLE) 的潜在治疗方法。然而，IL-2 给药可能涉及扩大不必要的促炎细胞的风险。我们在此研究了 IL-2 对 CD3/CD28 共刺激后 Treg 发育时 CD4 和 CD8 T 细胞产生促炎细胞因子的影响。虽然 SLE 患者的 Treg 细胞耗竭，但它们的 CD4 T 细胞准备接收和激活 IL-2 信号，这表现在 Treg 分化过程中 CD25 的上调和增强的 IL-2 诱导的 STAT5 磷酸化。然而，在 SLE 患者中，IL-2 还扩增了能够产生白细胞介素-5、白细胞介素-13 (IL-13) 和干扰素-γ (IFN-γ) 的 CD8 T 细胞，这伴随着 GATA-3 的表达增强和 STAT6 的磷酸化，但不是 STAT5。我们的数据为系统性给予 IL-2 提供了一个安全性信号，并挑战了长期以来的 1 型和 2 型细胞因子拮抗的概念平台，新记录了 SLE 中 IL-2 依赖性 IL-13 和 IFN-γ 双阳性 (IL-13IFNγ) CD8 T 细胞的发育。
