Department of Rheumatology and Immunology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China.
Cell Rep. 2020 May 12;31(6):107621. doi: 10.1016/j.celrep.2020.107621.
Follicular helper T cells (Tfhs) are essential for germinal center (GC) B cell maturation and antibody development. However, the intrinsic mechanisms that regulate Tfh differentiation are largely unknown. Here, we demonstrate that the frequencies of Tfhs and GC B cells, as well as interleukin-21 (IL-21) and anti-ovalbumin (OVA) antibodies, are markedly decreased in forkhead box O3 (Foxo3) knockout mice immunized with OVA. Using mixed bone marrow chimeras and lymphocyte-repopulated Rag1 mice proves that wild-type (WT), but not Foxo3-deficient T cells provoke GC B cell maturation and antibody production. Deficiency of Foxo3 inhibits inducible T cell co-stimulator (ICOS)-induced Tfh differentiation. Chromatin immunoprecipitation assay results suggest that Foxo3 is able to bind to the IL-21 promoter and regulate IL-21 secretion. In conclusion, our study unveils a critical role of Foxo3 in the regulation of Tfh differentiation and IL-21 production. Modulating Foxo3 activity may be beneficial for enhancing or preventing antibody-mediated immune responses.
滤泡辅助 T 细胞（Tfh）对于生发中心（GC）B 细胞成熟和抗体产生是必需的。然而，调节 Tfh 分化的内在机制在很大程度上尚不清楚。在这里，我们证明在卵清蛋白（OVA）免疫的叉头框 O3（Foxo3）敲除小鼠中，Tfh 和 GC B 细胞以及白细胞介素-21（IL-21）和抗 OVA 抗体的频率明显降低。使用混合骨髓嵌合体和淋巴细胞再植入 Rag1 小鼠证明，野生型（WT）而非 Foxo3 缺陷 T 细胞可引发 GC B 细胞成熟和抗体产生。Foxo3 的缺乏抑制诱导型 T 细胞共刺激物（ICOS）诱导的 Tfh 分化。染色质免疫沉淀分析结果表明，Foxo3 能够结合到 IL-21 启动子并调节 IL-21 的分泌。总之，我们的研究揭示了 Foxo3 在调节 Tfh 分化和 IL-21 产生中的关键作用。调节 Foxo3 的活性可能有益于增强或预防抗体介导的免疫反应。
