Regenerating islet-derived III-gamma regulates pulmonary Th17 immunity by altering the gut microbiome (P3164)

Abstract Commensal microbes are critical for the development of intestinal lymphoid tissues, but little is known about how they shape systemic immunity. Lung infection with Aspergillus fumigatus induces a potent IL-17 response from T cells. Vancomycin drinking water diminished lung il17a expression during infection, demonstrating a role for gram-positive commensals in amplifying pulmonary immunity. Since RegIIIγ is an intestinal anti-microbial factor that targets gram-positive bacteria, we hypothesized that it would decrease lung Th17 cytokine expression, similar to the effects of oral vancomycin. To test this, RegIIIγ-/- mice and C57BL/6 (WT) mice were infected with A. fumigatus, and lung cytokines were analyzed two days later. RegIIIγ-/- mice had elevated expression of il17a, il17f and il22, and this was positively correlated with intestinal colonization by segmented filamentous bacteria. Further, reconstitution of il22-/- mice with recombinant RegIIIγ by oral gavage decreased steady-state IL-17+ γδ T cells in the lung. To test if RegIIIγ regulates lung Th17 priming by interacting with intestinal microbiota, mice were treated with vancomycin water and then immunized with OVA plus cholera toxin. Notably, antibiotic treatment reduced lung Th17 numbers in RegIIIγ-/- mice to the level observed in WT mice. These data demonstrate that modulating the expression of an intestinal anti-bacterial lectin can have profound effects on pulmonary immunity by altering the gut microbiome.