title: Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine.
abstract: T(H)17 cells are a lineage of CD4(+) T cells that are critical for host defense and autoimmunity by expressing the cytokines IL-17A, IL-17F, and IL-22. A feature of T(H)17 cells at steady state is their ubiquitous presence in the lamina propria of the small intestine. The induction of these steady-state intestinal T(H)17 (sT(H)17) cells is dependent on the presence of the microbiota. However, the signaling pathway linking the microbiota to the development of intestinal sT(H)17 cells remains unclear. In this study, we show that IL-1β, but not IL-6, is induced by the presence of the microbiota in intestinal macrophages and is required for the induction of sT(H)17 cells. In the absence of IL-1β-IL-1R or MyD88 signaling, there is a selective reduction in the frequency of intestinal sT(H)17 cells and impaired production of IL-17 and IL-22. Myeloid differentiation factor 88-deficient (MyD88(-/-)) and germ-free (GF) mice, but not IL-1R(-/-) mice, exhibit impairment in IL-1β induction. Microbiota-induced IL-1β acts directly on IL-1R-expressing T cells to drive the generation of sT(H)17 cells. Furthermore, administration of IL-1β into GF mice induces the development of retinoic acid receptor-related orphan receptor γt-expressing sT(H)17 cells in the small intestine, but not in the spleen. Thus, commensal-induced IL-1β production is a critical step for sT(H)17 differentiation in the intestine, which may have therapeutic implications for T(H)17-mediated pathologies.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Shaw
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Yun-Gi
authors.initials: YG
authors.lastname: Kim
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018398:Homeodomain Proteins / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D007378:Interleukins / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology*; D008264:Macrophages / Q000382:microbiology; D054892:Metagenome / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D018398:Homeodomain Proteins; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D007378:Interleukins; D000097043:Interleukin-22; C064658:RAG-1 protein