Abstract

The intracellular fragment of Notch1, a mediator of Notch signaling that is frequently detected in thymic immigrants, is critical for specifying T-cell fate in the thymus, where Delta-like 4 (Dll4) functions as a Notch ligand on the epithelium. However, as such Notch signaling has not been detected in mature T cells, how Notch signaling contributes to their response in secondary lymphoid organs has not yet been fully defined. Here, we detected the marked expression of Dll4 on the stromal cells and the active fragment of Notch1 (Notch1 intracellular domain, N1ICD) in CD4⁺ T cells in the follicles of Peyer’s patches (PPs). In addition, N1ICD-bearing T cells were found in the T-cell zone of PPs, especially in the transcription factor Foxp3⁺ regulatory T (Treg) cells, with slight expression of Dll4 on the stromal cells. These fragments disappeared in Dll4-deficient conditions. It was also found that Notch1- and Notch2-deficient T cells preferentially differentiated into Treg cells in PPs, but not CXCR5⁺PD-1⁺ follicular helper T (Tfh) cells. Moreover, these phenotypes were also observed in chimeric mice reconstituted with the control and T-cell-specific Notch1/2-deficient bone marrow or Treg cells. These results demonstrated that Dll4-mediated Notch signaling in PPs is required for the efficient appearance of Tfh cells in a Treg cell-prone environment, which is common among the gut-associated lymphoid tissues, and is critical for the generation of Tfh-mediated germinal center B cells.

中文翻译：

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Notch 信号支持在 Peyer 斑块中出现滤泡辅助性 T 细胞，同时减少调节性 T 细胞

摘要

Notch1 的细胞内片段是一种在胸腺迁移中经常检测到的 Notch 信号传导介质，对于指定胸腺中的 T 细胞命运至关重要，其中 Delta-like 4 (Dll4) 作为上皮细胞上的 Notch 配体发挥作用。然而，由于尚未在成熟 T 细胞中检测到此类 Notch 信号传导，因此 Notch 信号传导如何有助于它们在次级淋巴器官中的反应尚未完全确定。^{在这里，我们检测到基质细胞上 Dll4 的显着表达和派尔斑 (PPs) 滤泡中 CD4 +} T 细胞中Notch1 的活性片段（Notch1 胞内结构域，N1ICD ）。此外，在 PPs 的 T 细胞区发现了携带 N1ICD 的 T 细胞，特别是在转录因子 Foxp3 ⁺调节性 T (Treg) 细胞，在基质细胞上有轻微的 Dll4 表达。这些片段在Dll4缺陷条件下消失了。还发现Notch1和Notch2缺陷的T细胞优先分化为PPs中的Treg细胞，而不是CXCR5 ⁺ PD-1 ⁺滤泡辅助 T (Tfh) 细胞。此外，在用对照和 T 细胞特异性 Notch1/2 缺陷型骨髓或 Treg 细胞重组的嵌合小鼠中也观察到了这些表型。这些结果表明，PPs 中 Dll4 介导的 Notch 信号是 Tfh 细胞在易发生 Treg 细胞的环境中有效出现所必需的，这在肠道相关淋巴组织中很常见，并且对于 Tfh 介导的生发的产生至关重要。中心 B 细胞。