Department of Neurology, Thomas Jefferson University, 900 Walnut Street, Suite 300, Philadelphia, PA, 19107, USA.
J Neuroinflammation. 2024 Oct 8;21(1):253. doi: 10.1186/s12974-024-03224-2.
The IL-7 receptor alpha (IL-7Rα) binds both IL-7 and thymic stromal lymphopoietin (TSLP). IL-7Rα is essential for the development and survival of naive CD4 T cells and their differentiation to effector/memory CD4 T cells. Mice lacking IL-7Rα have severe lymphopenia and are resistant to experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. However, it has been reported that IL-7Rα on peripheral CD4 T cells is disposable for their maintenance and EAE pathogenesis, which does not align with the body of knowledge on the role of IL-7Rα in the biology of CD4 T cells. Given that a definitive study on this important topic is lacking, we revisited it using a novel approach, an inducible knockout of the IL-7Rα gene in CD4 T cells.
We generated Il7ra/CD4CreER double transgenic mouse line (henceforth CD4), susceptible to tamoxifen-induced knockout of the IL-7Rα gene in CD4 T cells. CD4 mice were immunized with MOG for EAE induction and monitored for disease development. The expression of IL-7Rα, CD4 T cell numbers, and MOG-specific CD4 T cell response was evaluated in the central nervous system (CNS) and lymphoid tissues by flow cytometry. Additionally, splenocytes of CD4 mice were stimulated with MOG to assess their proliferative response and cytokine production by T helper cells.
Loss of IL-7Rα from the surface of CD4 T cells in CD4 mice was virtually complete several days after tamoxifen treatment. The loss of IL-7Rα in CD4 T cells led to a gradual and substantial decrease in their numbers in both non-immunized and immunized CD4 mice, followed by slow repopulation up to the initial numbers. CD4 mice did not develop EAE. We found a decrease in the total numbers of TNF-, IFN-γ-, IL-17 A-, and GM-CSF-producing CD4 T cells and regulatory T cells in the spleens and CNS of immunized CD4 mice. Tracking MOG-specific CD4 T cells revealed a significant reduction in their numbers in CD4 mice and decreased proliferation and cytokine production in response to MOG.
Our study demonstrates that IL-7Rα on peripheral CD4 T cells is essential for their maintenance, immune response, and EAE pathogenesis.
白细胞介素 7 受体α(IL-7Rα)既能结合白细胞介素 7(IL-7),也能结合胸腺基质淋巴细胞生成素(TSLP)。IL-7Rα 对于初始 CD4 T 细胞的发育和存活及其向效应/记忆 CD4 T 细胞的分化至关重要。缺乏 IL-7Rα 的小鼠会出现严重的淋巴细胞减少症,并对实验性自身免疫性脑脊髓炎(EAE)产生抗性,EAE 是多发性硬化症的一种模型。然而,有报道称外周血 CD4 T 细胞上的 IL-7Rα 对于其维持和 EAE 发病机制是可丢弃的,这与 IL-7Rα 在 CD4 T 细胞生物学中的作用的知识体系不一致。鉴于此重要问题缺乏明确的研究,我们使用一种新方法,即诱导性敲除 CD4 T 细胞中的 IL-7Rα 基因,重新进行了研究。
我们构建了白细胞介素 7 受体α/CD4CreER 双转基因小鼠品系(简称 CD4),该品系对 CD4 T 细胞中 IL-7Rα 基因的诱导型敲除敏感。用髓鞘少突胶质细胞糖蛋白(MOG)对 CD4 小鼠进行免疫,以诱导 EAE,并监测疾病进展。通过流式细胞术评估中枢神经系统(CNS)和淋巴组织中 IL-7Rα 的表达、CD4 T 细胞数量以及 MOG 特异性 CD4 T 细胞反应。此外,用 MOG 刺激 CD4 小鼠的脾细胞,以评估辅助性 T 细胞的增殖反应和细胞因子产生情况。
在 CD4 小鼠中,CD4 T 细胞表面的 IL-7Rα 在他莫昔芬处理后几天几乎完全消失。CD4 T 细胞中 IL-7Rα 的缺失导致其数量在非免疫和免疫的 CD4 小鼠中逐渐显著减少,随后缓慢重新增殖至初始数量。CD4 小鼠未发生 EAE。我们发现免疫的 CD4 小鼠的脾脏和 CNS 中 TNF-α、IFN-γ、IL-17A 和 GM-CSF 产生的 CD4 T 细胞和调节性 T 细胞总数减少。对 MOG 特异性 CD4 T 细胞进行跟踪,发现 CD4 小鼠的细胞数量显著减少,对 MOG 的增殖反应和细胞因子产生减少。
我们的研究表明,外周血 CD4 T 细胞上的 IL-7Rα 对于其维持、免疫反应和 EAE 发病机制是必不可少的。