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Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.

Original publication

DOI

10.1016/j.immuni.2018.12.020

Type

Journal article

Journal

Immunity

Publication Date

19/02/2019

Volume

50

Pages

446 - 461.e9

Keywords

IL-17, IL-22, Mincle, Syk kinase, T lymphocyte, antimicrobial defense, dendritic cell, gut microbiota translocation, innate lymphoid cells, intestinal barrier, lipid metabolism, liver inflammation, Animals, Dendritic Cells, Gastrointestinal Microbiome, Humans, Interleukin-17, Interleukins, Intestinal Mucosa, Lectins, C-Type, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Peyer's Patches, Signal Transduction, Syk Kinase, Th17 Cells, Interleukin-22