Abstract
The regional specialization of intestinal immune cells is affected by the longitudinal heterogeneity of environmental factors. Although the distribution of group 3 innate lymphoid cells (ILC3s) is well characterized in the lamina propria, it is poorly defined in Peyer’s patches (PPs) along the intestine. Given that PP ILC3s are closely associated with mucosal immune regulation, it is important to characterize the regulatory mechanism of ILC3s. Here, we found that terminal ileal PPs of specific pathogen-free (SPF) mice have fewer NKp46+ ILC3s than jejunal PPs, while there was no difference in NKp46+ ILC3 numbers between terminal ileal and jejunal PPs in antibiotics (ABX)-treated mice. We also found that butyrate levels in the terminal ileal PPs of SPF mice were higher than those in the jejunal PPs of SPF mice and terminal ileal PPs of ABX-treated mice. The reduced number of NKp46+ ILC3s in terminal ileal PPs resulted in a decrease in Csf2 expression and, in turn, resulted in reduced regulatory T cells and enhanced antigen-specific T-cell proliferation. Thus, we suggest that NKp46+ ILC3s are negatively regulated by microbiota-derived butyrate in terminal ileal PPs and the reduced ILC3 frequency is closely associated with antigen-specific immune induction in terminal ileal PPs.
Highlights
The gastrointestinal tract has a unique immune system that is specialized to the gut microenvironment[1]
Germ-free mice have been shown to exhibit a decrease in IL-22-expressing NKp46+ ILC3s36, whereas other studies have shown that the microbiota plays a role as a negative regulator of ILC3s in the lamina propria (LP) of the small intestine[33]
Among various metabolites produced by microorganisms, retinoic acid, which is concentrated primarily in the small intestine, drives the maintenance of receptor γt (RORγt)+ ILC3s, while it suppresses the expansion of ILC2s37
Summary
The gastrointestinal tract has a unique immune system that is specialized to the gut microenvironment[1]. While Lactobacillus, Streptococcus, and Enterococcus are localized primarily in the jejunum, segmented filamentous bacteria, Enterobacteriaceae, Bacteroides, and Clostridium are found mainly in the ileum and proximal colon[5] This longitudinal heterogeneity of microbes in the intestinal tract gives rise to regional specialization in the intestinal microenvironment, through the differential distribution of metabolites, such that aryl hydrocarbon receptor (AHR) ligands and short-chain fatty acids (SCFAs) are present decreasingly and increasingly, respectively, upon descending through the intestinal tract[6, 7]. PP ILC3s were shown to inhibit the proliferation of Alcaligenes spp.-specific CD4+ T cells in terminal ileal PPs and this inhibition was closely associated with the control of systemic inflammation induced by microbiota[29] These findings suggest regulatory roles of ILCs in connecting and regulating innate and adaptive immune responses in PPs, the regulatory mechanism of ILCs in PPs has not yet been clearly defined. We sought to understand the regulatory role of butyrate on ILC3s in PPs, especially in relation to the anatomical differential distribution of ILC3s in jejunal and terminal ileal PPs and its biological consequences in mucosal immune regulation
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