Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis.
Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis.
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DOI：
10.1186/s12974-021-02076-4
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发表时间：
2021-01-19
影响因子：
9.3
通讯作者：
Leavenworth JW
中科院分区：
文献类型：
--
作者：
Luo L;Hu X;Dixon ML;Pope BJ;Leavenworth JD;Raman C;Meador WR;Leavenworth JW
滤泡调节性 T (TFR) 细胞对于生发中心 (GC) 反应和体液自我耐受的调节至关重要。继发于功能失调的 TFR 细胞的卵泡辅助 T (TFH) 细胞-GC-抗体 (Ab) 反应失调是一系列自身免疫性疾病的根源。 TFR 细胞对多发性硬化症 (MS) 和小鼠实验性自身免疫性脑脊髓炎 (EAE) 发病机制的贡献目前尚不清楚。为了确定失调的调节性 T 细胞 (Treg)、TFR 细胞和 Ab 反应对 EAE 的影响，我们将 MOG 诱导的小鼠 EAE 与转录因子 Blimp1 的 FoxP3 特异性消融与对照小鼠进行了比较。体外共培养测定用于了解 Tregs 和 Ab 如何调节小胶质细胞和中枢神经系统 (CNS) 浸润性骨髓细胞的活性。与对照小鼠相比，具有 FoxP3 特异性缺失 Blimp1 的小鼠出现了严重的 EAE，并且未能恢复，这反映出 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 TFH-Ab 反应增加、中枢神经系统中更多 IgE 沉积以及无法调节中枢神经系统 CD11b+ 骨髓细胞相关。值得注意的是，血清 IgE 滴度与 EAE 评分呈正相关，用这些 EAE 小鼠的血清培养 CNS CD11b+ 细胞可增强其活化，而 Blimp1 缺陷型 TFR 细胞的转移则促进 Ab 产生、CNS CD11b+ 细胞活化和 EAE。 Blimp1 对于 EAE 中 TFR 细胞和抗体反应的维持至关重要。 TFR 细胞和抗体反应失调会促进中枢神经系统自身免疫。在线版本包含可在 10.1186/s12974-021-02076-4 获取的补充材料。
Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR 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), TFR 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 TFH-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 TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity. The online version contains supplementary material available at 10.1186/s12974-021-02076-4.
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影响因子：
30.5
作者：
Clement, Rachel L.;Daccache, Joe;Sage, Peter T.
通讯作者：
Sage, Peter T.
影响因子：
15.9
作者：
Haak, Stefan;Croxford, Andrew L.;Waisman, Ari
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控制FOXP3基因座中的顺式元素对调节T细胞身份的遗传控制。
影响因子：
64.5
作者：
Feng Y;Arvey A;Chinen T;van der Veeken J;Gasteiger G;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
32.4
作者：
Croxford, Andrew L.;Lanzinger, Margit;Becher, Burkhard
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影响因子：
32.4
作者：
Bailey-Bucktrout, Samantha L.;Martinez-Llordella, Marc;Zhou, Xuyu;Anthony, Bryan;Rosenthal, Wendy;Luche, Herve;Fehling, Hans J.;Bluestone, Jeffrey A.
通讯作者：
Bluestone, Jeffrey A.