Division of Immune and Infectious Diseases, CHU de Québec Research Center, Quebec City, Quebec, Canada.
ARThrite Center, Laval University, Quebec City, Quebec, Canada.
J Immunol. 2022 Mar 1;208(5):1115-1127. doi: 10.4049/jimmunol.2100550. Epub 2022 Feb 14.
Purinergic signaling plays a major role in T cell activation leading to IL-2 production and proliferation. However, it is unclear whether purinergic signaling contributes to the differentiation and activation of effector T cells. In this study, we found that the purinergic receptor P2X4 was associated with human Th17 cells but not with Th1 cells. Inhibition of P2X4 receptor with the specific antagonist 5-BDBD and small interfering RNA inhibited the development of Th17 cells and the production of IL-17 by effector Th17 cells stimulated via the CD3/CD28 pathway. Our results showed that P2X4 was required for the expression of retinoic acid-related orphan receptor C, which is the master regulator of Th17 cells. In contrast, inhibition of P2X4 receptor had no effect on Th1 cells and on the production of IFN-γ and it did not affect the expression of the transcription factor T-bet (T-box transcription factor). Furthermore, inhibition of P2X4 receptor reduced the production of IL-17 but not of IFN-γ by effector/memory CD4 T cells isolated from patients with rheumatoid arthritis. In contrast to P2X4, inhibition of P2X7 and P2Y receptors had no effects on Th17 and Th1 cell activation. Finally, treatment with the P2X4 receptor antagonist 5-BDBD reduced the severity of collagen-induced arthritis in mice by inhibiting Th17 cell expansion and activation. Our findings provide novel insights into the role of purinergic signaling in T cell activation and identify a critical role for the purinergic receptor P2X4 in Th17 activation and in autoimmune arthritis.
嘌呤能信号在 T 细胞激活中起主要作用，导致白细胞介素 2（IL-2）的产生和增殖。然而，嘌呤能信号是否有助于效应 T 细胞的分化和激活尚不清楚。在这项研究中，我们发现嘌呤能受体 P2X4 与人类 Th17 细胞有关，但与 Th1 细胞无关。用特异性拮抗剂 5-BDBD 和小干扰 RNA 抑制 P2X4 受体可抑制 Th17 细胞的发育和效应 Th17 细胞通过 CD3/CD28 途径刺激产生的白细胞介素 17（IL-17）。我们的结果表明，P2X4 是维甲酸相关孤儿受体 C（Th17 细胞的主调控因子）表达所必需的。相比之下，抑制 P2X4 受体对 Th1 细胞和 IFN-γ 的产生没有影响，也不影响转录因子 T 盒转录因子（T-bet）的表达。此外，抑制 P2X4 受体可减少类风湿关节炎患者效应/记忆 CD4 T 细胞产生的 IL-17，但不减少 IFN-γ。与 P2X4 相反，抑制 P2X7 和 P2Y 受体对 Th17 和 Th1 细胞的激活没有影响。最后，用 P2X4 受体拮抗剂 5-BDBD 治疗可通过抑制 Th17 细胞的扩增和激活，减轻胶原诱导性关节炎小鼠的严重程度。我们的研究结果为嘌呤能信号在 T 细胞激活中的作用提供了新的见解，并确定了嘌呤能受体 P2X4 在 Th17 激活和自身免疫性关节炎中的关键作用。
