Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

• Published in: Cell reports (Cambridge) Vol. 36; no. 8; p. 109608
• Main Authors: Sano, Teruyuki, Kageyama, Takahiro, Fang, Victoria, Kedmi, Ranit, Martinez, Carlos Serafin, Talbot, Jhimmy, Chen, Alessandra, Cabrera, Ivan, Gorshko, Oleksandra, Kurakake, Reina, Yang, Yi, Ng, Charles, Schwab, Susan R., Littman, Dan R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.08.2021; Elsevier
• Subjects: Animals; CD4 T cells; Cell Differentiation - immunology; Cell Differentiation - physiology; cytokine receptors; Cytokines - immunology; Cytokines - metabolism; Gastrointestinal Microbiome - immunology; Gastrointestinal Microbiome - physiology; homeostatic Th17 cells; IL-17A; ileum; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; Intestines - immunology; Lymph Nodes - immunology; Lymphocyte Activation - immunology; lymphocyte homing; Mice; mucosal immunology; nuclear receptors; Peyer’s patches; T cell activation; Th17 Cells - immunology; ileum; nuclear receptors; homeostatic Th17 cells; mucosal immunology; Peyer’s patches; T cell activation; IL-17A; CD4 T cells; cytokine receptors; lymphocyte homing
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109608

Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here, we show that intestine-draining mesenteric lymph nodes (MLNs), not intestine proper, are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their upregulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLNs and accumulation of the cells in the lamina propria. [Display omitted] •Early SFB-induced Th17 cell differentiation occurs in mLN, not Peyer’s patches•IL-6 is required for early RORγt expression by SFB-specific Th17 cells•IL-21 or IL-23 promote delayed differentiation of Th17 cells without IL-6•IL-6, IL-21, and IL-23 have distinct roles in production of Th17 effector cytokines Sano et al. show that cytokines IL-21 and IL-23, but not IL-1β, can replace IL-6 in guiding delayed gut commensal microbe-dependent Th17 cell differentiation in the mesenteric lymph node and subsequent accumulation of the cells in the small intestine lamina propria.