Abstract
The microbiota control regional immunity using mechanisms such as inducing IL-17A-producing γδ T (γδT-17) cells in various tissues. However, little is known regarding hepatic γδT cells that are constantly stimulated by gut commensal microbes. Here we show hepatic γδT cells are liver-resident cells and predominant producers of IL-17A. The microbiota sustain hepatic γδT-17 cell homeostasis, including activation, survival and proliferation. The global commensal quantity affects the number of liver-resident γδT-17 cells; indeed, E. coli alone can generate γδT-17 cells in a dose-dependent manner. Liver-resident γδT-17 cell homeostasis depends on hepatocyte-expressed CD1d, that present lipid antigen, but not Toll-like receptors or IL-1/IL-23 receptor signalling. Supplementing mice in vivo or loading hepatocytes in vitro with exogenous commensal lipid antigens augments the hepatic γδT-17 cell number. Moreover, the microbiota accelerate nonalcoholic fatty liver disease through hepatic γδT-17 cells. Thus, our work describes a unique liver-resident γδT-17 cell subset maintained by gut commensal microbes through CD1d/lipid antigens.
Highlights
The microbiota control regional immunity using mechanisms such as inducing IL-17Aproducing gd T cells in various tissues
They are liver resident without exchanging with circulating gdT cells (Fig. 1e and Supplementary Fig. 1a–c); second, hepatic gdT cells predominantly produce a high level of IL-17A (Fig. 1a–d); third, they recognize (Fig. 5e) and are promoted by (Figs 5c and 6d,e) CD1d/commensal lipid antigen
Skin gdT-17 cells are compartmentally controlled by the skin, but not gut, microbiota[27]; IL-1R signalling has an important role in microbiota-mediated IL-17A production by peritoneal cavity (PC) gdT cells[21]; IL-17A production by lung-resident gdT cells requires IL-6 signalling instead[29]; dermal gdT cells preferentially rely on IL-1 and MyD88 signalling to produce IL-17A30; the gdT-cell subtype in the colonic lamina propria produces
Summary
The microbiota control regional immunity using mechanisms such as inducing IL-17Aproducing gd T (gdT-17) cells in various tissues. Little is known regarding hepatic gdT cells that are constantly stimulated by gut commensal microbes. Liver-resident gdT-17 cell homeostasis depends on hepatocyte-expressed CD1d, that present lipid antigen, but not Toll-like receptors or IL-1/IL-23 receptor signalling. Supplementing mice in vivo or loading hepatocytes in vitro with exogenous commensal lipid antigens augments the hepatic gdT-17 cell number. The microbiota accelerate nonalcoholic fatty liver disease through hepatic gdT-17 cells. Our work describes a unique liver-resident gdT-17 cell subset maintained by gut commensal microbes through CD1d/lipid antigens. A gdT cell subset in human blood can respond to CD1d-presented sulfatide, a lipid antigen present in both hosts and bacteria[11]. The microbiota maintain hepatic gdT-17 cell homeostasis, the underlying mechanism of which involves microbiota lipid antigens presented by hepatocyte-expressed CD1d, but not PAMPs or cytokine signals. Liverresident gdT cells responding to the microbiota contribute to nonalcoholic fatty liver disease (NAFLD)
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