Peyer’s patches (PPs) are lymphoid structures situated adjacent to the intestinal epithelium that support B cell responses that give rise to many intestinal IgA-secreting cells. Induction of isotype switching to IgA in PPs requires interactions between B cells and TGFβ-activating conventional dendritic cells type 2 (cDC2s) in the subepithelial dome (SED). However, the mechanisms promoting cDC2 positioning in the SED are unclear. Here, we found that PP cDC2s express GPR35, a receptor that promotes cell migration in response to various metabolites, including 5-hydroxyindoleacetic acid (5-HIAA). In mice lacking GPR35, fewer cDC2s were found in the SED, and frequencies of IgA⁺ germinal center (GC) B cells were reduced. IgA plasma cells were reduced in both the PPs and lamina propria. These phenotypes were also observed in chimeric mice that lacked GPR35 selectively in cDCs. GPR35 deficiency led to reduced coating of commensal bacteria with IgA and reduced IgA responses to cholera toxin. Mast cells were present in the SED, and mast cell–deficient mice had reduced PP cDC2s and IgA⁺ cells. Ablation of tryptophan hydroxylase 1 (Tph1) in mast cells to prevent their production of 5-HIAA similarly led to reduced PP cDC2s and IgA responses. Thus, mast cell–guided positioning of GPR35⁺ cDC2s in the PP SED supports induction of intestinal IgA responses.

中文翻译：

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肥大细胞帮助组织派尔氏集结生态位以诱导 IgA 反应

派尔氏淋巴集结 (PP) 是位于肠上皮附近的淋巴结构，支持 B 细胞反应，从而产生许多肠道 IgA 分泌细胞。 PP 中同种型转换为 IgA 的诱导需要 B 细胞与上皮下圆顶 (SED) 中 TGFβ 激活的常规 2 型树突状细胞 (cDC2) 之间的相互作用。然而，促进 cDC2 在 SED 中定位的机制尚不清楚。在这里，我们发现 PP cDC2 表达 GPR35，这是一种响应各种代谢物（包括 5-羟基吲哚乙酸 (5-HIAA)）而促进细胞迁移的受体。在缺乏 GPR35 的小鼠中，SED 中发现的 cDC2 较少，并且 IgA ⁺生发中心 (GC) B 细胞的频率降低。 PP 和固有层中的 IgA 浆细胞均减少。这些表型也在 cDC 中选择性缺乏 GPR35 的嵌合小鼠中观察到。 GPR35 缺陷导致共生细菌 IgA 涂层减少，并减少 IgA 对霍乱毒素的反应。 SED 中存在肥大细胞，肥大细胞缺陷小鼠的 PP cDC2 和 IgA ⁺细胞减少。消除肥大细胞中的色氨酸羟化酶 1 (Tph1) 以阻止其产生 5-HIAA，同样会导致 PP cDC2 和 IgA 反应减少。因此，肥大细胞引导 GPR35 ⁺ cDC2 在 PP SED 中的定位支持诱导肠道 IgA 反应。