Journal
IMMUNITY
Volume 50, Issue 2, Pages 446-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2018.12.020
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Funding
- Spanish Ministerio de Educacion [AP2010-5935]
- Spanish Ministerio de Ciencia, Innovacion, y Universidades (MCIU) [SAF2015-74561-JIN]
- Fondos Europeos de Desarrollo Regional (FEDER)
- Wellcome Trust
- MRC Centre for Medical Mycology at the University of Aberdeen
- Swiss National Science Foundation [PP00P3_150758]
- CNIC
- MCIU [SAF2016-79040-R, RD16/0015/0018-REEM]
- Agencia Estatal de Investigacion [SAF2016-79040-R]
- FEDER [SAF2016-79040-R, RD16/0015/0018-REEM]
- Comunidad de Madrid [B2017/BMD-3733 Immunothercan-CM]
- FIS-Instituto de Salud Carlos III [RD16/0015/0018-REEM]
- Acteria Foundation
- Constantes y Vitales prize (Atresmedia)
- La Marato de TV3 Foundation [201723]
- European Commission [635122-PROCROP H2020]
- European Research Council (ERC-2016-Consolidator Grant) [725091]
- Pro-CNIC Foundation
- Severo Ochoa Center of Excellence [SEV-2015-0505]
- Swiss National Science Foundation (SNF) [PP00P3_150758] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MR/N006364/1, MR/N006364/2] Funding Source: UKRI
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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 RegIII gamma 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.
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