School of Pharmacy, Nantong University, Nantong, 226001, Jiangsu, China.
Department of Neurosurgery, University of Alabama at Birmingham, 1600 6th Avenue South, CHB 118A, Birmingham, AL, 35233, USA.
J Neuroinflammation. 2021 Jan 19;18(1):27. doi: 10.1186/s12974-021-02076-4.
Follicular regulatory T (T) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (T) cell-GC-antibody (Ab) response secondary to dysfunctional T cells is the root of an array of autoimmune disorders. The contribution of T cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear.
To determine the impact of dysregulated regulatory T cells (Tregs), T cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells.
Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased T-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient T cells promoted Ab production, activation of CNS CD11b cells, and EAE.
Blimp1 is essential for the maintenance of T cells and Ab responses in EAE. Dysregulated T cells and Ab responses promote CNS autoimmunity.
滤泡调节性 T（T）细胞对于调节生发中心（GC）反应和体液自身耐受至关重要。由于 T 细胞功能障碍导致滤泡辅助性 T（T）细胞-GC-抗体（Ab）反应失调，是一系列自身免疫性疾病的根源。T 细胞在多发性硬化症（MS）和实验性自身免疫性脑脊髓炎（EAE）中的发病机制中的作用仍很大程度上不清楚。
为了确定失调的调节性 T 细胞（Tregs）、T 细胞和 Ab 反应对 EAE 的影响，我们比较了 FoxP3 特异性缺失转录因子 Blimp1 的小鼠与对照小鼠之间的 MOG 诱导的 EAE。体外共培养实验用于了解 Tregs 和 Ab 如何调节小胶质细胞和中枢神经系统（CNS）浸润髓样细胞的活性。
与对照小鼠相比，FoxP3 特异性缺失 Blimp1 的小鼠发生严重的 EAE 且无法恢复，这反映了 Tregs 转化为白细胞介素（IL）-17A/粒细胞-巨噬细胞集落刺激因子（GM-CSF）产生的效应 T 细胞，与增加的 T-Ab 反应、CNS 中更多的 IgE 沉积以及无法调节 CNS CD11b 髓样细胞有关。值得注意的是，血清 IgE 滴度与 EAE 评分呈正相关，并且从这些 EAE 小鼠的血清中培养 CNS CD11b 细胞增强了其激活，而转移 Blimp1 缺陷型 T 细胞促进了 Ab 产生、CNS CD11b 细胞的激活和 EAE。
Blimp1 对于 EAE 中的 T 细胞和 Ab 反应的维持至关重要。失调的 T 细胞和 Ab 反应促进了中枢神经系统自身免疫。
