Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor
Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor
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DOI：
10.1016/j.celrep.2019.10.012
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发表时间：
2019-11-12
期刊：
影响因子：
8.8
通讯作者：
Leavenworth, Jianmei W.
中科院分区：
文献类型：
--
作者：
Wang, Lei;Shen, Erxia;Leavenworth, Jianmei W.
滤泡调节性T细胞（Follicular Regulatory T cells，T-FR）是一种特殊的抑制性T细胞亚群，它控制着生发中心（germinal center，GC）的反应并维持体液自身耐受。维持TFR谱系特性和抑制活性的机制在很大程度上仍然未知。在这里，我们发现FoxP 3（+）T-FR细胞表达Blimp 1对于TFR谱系稳定、进入GC和表达调节活性是必不可少的。T-FR细胞中Blimp 1的缺失降低了FoxP 3和CTLA-4的表达，增加了促炎细胞因子和自身抗体的自发产生，包括IgE升高。T-FR稳定性的维持反映了IL-23 R-STAT 3轴的Blimp 1依赖性抑制和CD 25-STAT 5通路的激活，而IL-23 R-STAT 3沉默或STAT 5激活增加则挽救了Blimp 1缺陷的T-FR表型。Blimp 1依赖的CXCR 5/CCR 7表达控制也调节T-FR归巢到GC。这些发现揭示了Blimp 1依赖的T-FR检查点，该检查点执行抑制活性并充当GC进入的看门人。
Follicular regulatory T (T-FR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain TFR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3(+) T-FR cells is essential for TFR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in T-FR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoanti-bodies, including elevated IgE. Maintenance of T-FR stability reflected Blimp1-dependent repression of the IL-23R-STAT3 axis and activation of the CD25-STAT5 pathway, while silenced IL-23R-STAT3 or increased STAT5 activation rescued the Blimp1-deficient T-FR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated T-FR homing into the GC. These findings uncover a Blimp1-dependent T-FR checkpoint that enforces suppressive activity and acts as a gatekeeper of GC entry.