Abstract
In humans and mice, mucosal immune responses are dominated by IgA antibodies and the cytokine TGF-β, suppressing unwanted immune reactions but also targeting Ig class switching to IgA. It had been suggested that eosinophils promote the generation and maintenance of mucosal IgA-expressing plasma cells. Here, we demonstrate that not eosinophils, but specific bacteria determine mucosal IgA production. Co-housing of eosinophil-deficient mice with mice having high intestinal IgA levels, as well as the intentional microbiota transfer induces TGF-β expression in intestinal T follicular helper cells, thereby promoting IgA class switching in Peyer's patches, enhancing IgA+ plasma cell numbers in the small intestinal lamina propria and levels of mucosal IgA. We show that bacteria highly enriched for the genus Anaeroplasma are sufficient to induce these changes and enhance IgA levels when adoptively transferred. Thus, specific members of the intestinal microbiota and not the microbiota as such regulate gut homeostasis, by promoting the expression of immune-regulatory TGF-β and of mucosal IgA.
Highlights
Antibodies of the IgA isotype are dominant at mucosal surfaces in humans and mice
The absolute number of IgA+B220− plasma cells (1.28 ± 0.34 × 105) was more than 10fold lower in the small intestinal lamina propria (siLP) of non-cohoused dblGATA-1 mice when compared to BALB/c mice (15.11 ± 2.30 × 105; Fig. 1B and C), and in the Peyer’s patches (PP) of non-cohoused dblGATA-1 mice the numbers of IgA+PNAhiB220+ GC B cells were more than 20-fold lower than in non-cohoused BALB/c mice (6.50 ± 1.29 × 103 vs. 145.1 ± 30.3 × 103; Fig. 1D, E, and G)
Eosinophil-deficient dblGATA-1 mice had been described to be impaired for mucosal IgA [14,15], the role of differences in the microbiota between dblGATA-1 and their WT BALB/c counterpart were not considered in these studies
Summary
Antibodies of the IgA isotype are dominant at mucosal surfaces in humans and mice. IgA antibodies are an integral part of the mucosal barrier, controlling the growth and attachment of specific bacteria [1]. Ig class switching to IgA occurs mainly in GC reactions of Peyer’s patches (PP) [2], but can occur in mesenteric lymph nodes, in isolated lymphoid follicles and in the small intestinal lamina propria (siLP), where B cells are activated without the help of T cells [3,4,5]. In PP, the class switch to IgA is regulated by T follicular helper (Tfh) cells expressing TGF-β and IL-21 [11,12] and by dendritic cells activating latent TGF-β [13]. It has been reported that dblGATA-1 mice, which lack eosinophils [16], have reduced numbers of IgA+ GC B cells in their PP, reduced numbers of IgA-expressing plasma cells in their siLP, and lower levels of mucosal IgA than WT mice [14, 15]. We report that allowing the exchange of microbiota by cohousing equalizes their levels of mucosal IgA
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