Pulmonary Th17 immunity is regulated by regenerating islet-derived III-gamma and the gut microbiome (MUC4P.826)

Antimicrobial proteins provide an innate immune barrier against pathogen invasion. Here we identify a function for the bactericidal lectin regenerating islet-derived III-gamma (RegIIIγ) in shaping CD4 T cell polarization. Gram-positive bacteria in the intestine induce RegIIIγ expression, which modulates the immune tone of the gut, resulting in decreased Th17-type immunity during pulmonary fungal infection. This was associated with RegIIIγ inhibiting intestinal colonization with segmented filamentous bacteria (SFB), a pro-inflammatory commensal that augments Th17 differentiation. Vancomycin drinking water inhibited IL-17 production in lungs of RegIIIγ-/- and Il22-/- mice, demonstrating that intestinal Gram-positive commensals contribute to systemic inflammation. Reconstituting Il22-/- mice with IL-22 decreased the SFB/Clostridium ratio, while gastrointestinal delivery of recombinant RegIIIγ decreased inflammatory gene expression in lung tissue and protected Il22-/- mice from weight-loss during Aspergillus fumigatus infection. Therefore, intestinal antimicrobial proteins influence the development of adaptive immunity by altering the balance of pro- and anti-inflammatory intestinal commensal species.