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Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα₃) produced by RORγt⁺ innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα₁β₂) produced by RORγt⁺ ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt⁺ cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxin s produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.

Broad-spectrum antibiotics are widely used with patients in intensive care units (ICUs), many of whom develop hospital-acquired infections with Pseudomonas aeruginosa. Although preceding antimicrobial therapy is known as a major risk factor for P. aeruginosa-induced pneumonia, the underlying mechanisms remain incompletely understood. Here we demonstrate that depletion of the resident microbiota by broad-spectrum antibiotic treatment inhibited TLR-dependent production of a proliferation-inducing ligand (APRIL), resulting in a secondary IgA deficiency in the lung in mice and human ICU patients. Microbiota-dependent local IgA contributed to early antibacterial defense against P. aeruginosa. Consequently, P. aeruginosa-binding IgA purified from lamina propria culture or IgA hybridomas enhanced resistance of antibiotic-treated mice to P. aeruginosa infection after transnasal substitute. Our study provides a mechanistic explanation for the well-documented risk of P. aeruginosa infection following antimicrobial therapy, and we propose local administration of IgA as a novel prophylactic strategy.

Innate lymphoid cells are vital for the development of gut-associated lymphoid tissues, maintenance of the epithelial barrier, and protection against intestinal microbes; their dysfunction can promote immune pathology. Immunoglobulin A (IgA) production is important for maintenance of the gut epithelial barrier and the composition of the gut microbiota. Through the generation of knockout mouse models, Kruglov et al. (p. 1243 ) were able to distinguish how soluble and membrane-bound lymphotoxins expressed by innate lymphoid cells in the gut specifically regulate IgA production and thereby control gut microbiota composition. Soluble lymphotoxin plays a paracrine role in controlling immunoglobulin A responses and regulating gut microbiota. Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα 3 ) produced by RORγt + innate lymphoid cells (ILCs) controls T cell–dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα 1 β 2 ) produced by RORγt + ILCs is critical for T cell–independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt + cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.

Innate lymphoid cells are vital for the development of gut-associated lymphoid tissues, maintenance of the epithelial barrier, and protection against intestinal microbes; their dysfunction can promote immune pathology. Immunoglobulin A (IgA) production is important for maintenance of the gut epithelial barrier and the composition of the gut microbiota. Through the generation of knockout mouse models, Kruglov et al. (p. 1243) were able to distinguish how soluble and membrane-bound lymphotoxins expressed by innate lymphoid cells in the gut specifically regulate IgA production and thereby control gut microbiota composition. [PUBLICATION ABSTRACT] Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt+ innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα1β2) produced by RORγt+ ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt+ cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition. [PUBLICATION ABSTRACT]