Mast cells help organize the Peyer's patch niche for induction of IgA responses.

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. Editor's summary: IgA production by B cells in the gut is required for host defense against mucosal pathogens. Isotype switching to IgA in the subepithelial dome (SED) of Peyer's patches (PPs) requires B cell interactions with conventional dendritic cells type 2 (cDC2s), but how cDC2s are positioned in the SED is not understood. De Giovanni et al. show that in mice, GPR35-expressing cDC2s are recruited to the SED by 5-HIAA produced by mast cells. Positioning of GPR35⁺ αvβ8⁺ cDC2s in the SED was required for IgA class switching and intestinal IgA responses. These findings identify mast cells as organizers of cDC2 positioning within the SED. —Hannah Isles [ABSTRACT FROM AUTHOR]