IL-22 plays a crucial role in mucosal host defense against Gram-negative bacterial pneumonia. The study shows that IL-22, produced by T helper type 17 (TH17) cells, enhances the expression of host defense genes and increases the clonogenic potential of bronchial epithelial cells. IL-22 also increases transepithelial resistance to injury, which is essential for maintaining epithelial barrier function. In contrast, IL-17A is primarily involved in neutrophil recruitment and granulopoiesis. However, IL-22 is more critical for host defense against extracellular pathogens at mucosal sites. In an experimental model of Gram-negative pneumonia, IL-22 was produced in a time-dependent manner, similar to IL-17A and IL-17F, and was regulated by IL-23. Neutralization of IL-22 resulted in increased bacterial dissemination from the lung, which was exacerbated by the absence of IL-17A. IL-22 also increased the expression of host defense genes in mouse lung epithelium, with lipocalin-2 being required for IL-22-augmented antimicrobial activity. The study also shows that IL-22 is essential for the regulation of pulmonary IL-6 and CCL3 production. In mice deficient in IL-17A, IL-22 was more important than IL-17A in regulating these cytokines. Additionally, IL-22 was crucial for IL-6 production in the lung, as both antibody to IL-22-treated WT and IL-17A-deficient mice had statistically significant reductions in BAL IL-6 abundance 24 hours after infection. IL-22 and IL-17A both regulate the expression of chemokines such as CXCL1, CXCL2, and CXCL9, which are important for recruiting immune cells to the site of infection. IL-22 also enhances the antimicrobial activity of lung epithelial cells, as demonstrated by the increased killing of K. pneumoniae in vitro. This effect was dependent on the expression of lipocalin-2, which is involved in the innate immune response by sequestering iron from bacterial organisms. The study also shows that T cells from explanted cystic fibrosis lymph nodes produce IL-22, which may contribute to the increased susceptibility to bacterial infections in these individuals. Additionally, IL-22 responses are significantly elevated in lung lymphoid tissue from human subjects with cystic fibrosis, which may explain why bacteremia with P. aeruginosa is rare in these individuals. Overall, the study highlights the important role of IL-22 in mucosal host defense against Gram-negative bacterial infection. IL-22, produced by TH17 cells, is crucial for maintaining epithelial barrier function and enhancing antimicrobial activity. These findings support the concept that the TH1IL-22 plays a crucial role in mucosal host defense against Gram-negative bacterial pneumonia. The study shows that IL-22, produced by T helper type 17 (TH17) cells, enhances the expression of host defense genes and increases the clonogenic potential of bronchial epithelial cells. IL-22 also increases transepithelial resistance to injury, which is essential for maintaining epithelial barrier function. In contrast, IL-17A is primarily involved in neutrophil recruitment and granulopoiesis. However, IL-22 is more critical for host defense against extracellular pathogens at mucosal sites. In an experimental model of Gram-negative pneumonia, IL-22 was produced in a time-dependent manner, similar to IL-17A and IL-17F, and was regulated by IL-23. Neutralization of IL-22 resulted in increased bacterial dissemination from the lung, which was exacerbated by the absence of IL-17A. IL-22 also increased the expression of host defense genes in mouse lung epithelium, with lipocalin-2 being required for IL-22-augmented antimicrobial activity. The study also shows that IL-22 is essential for the regulation of pulmonary IL-6 and CCL3 production. In mice deficient in IL-17A, IL-22 was more important than IL-17A in regulating these cytokines. Additionally, IL-22 was crucial for IL-6 production in the lung, as both antibody to IL-22-treated WT and IL-17A-deficient mice had statistically significant reductions in BAL IL-6 abundance 24 hours after infection. IL-22 and IL-17A both regulate the expression of chemokines such as CXCL1, CXCL2, and CXCL9, which are important for recruiting immune cells to the site of infection. IL-22 also enhances the antimicrobial activity of lung epithelial cells, as demonstrated by the increased killing of K. pneumoniae in vitro. This effect was dependent on the expression of lipocalin-2, which is involved in the innate immune response by sequestering iron from bacterial organisms. The study also shows that T cells from explanted cystic fibrosis lymph nodes produce IL-22, which may contribute to the increased susceptibility to bacterial infections in these individuals. Additionally, IL-22 responses are significantly elevated in lung lymphoid tissue from human subjects with cystic fibrosis, which may explain why bacteremia with P. aeruginosa is rare in these individuals. Overall, the study highlights the important role of IL-22 in mucosal host defense against Gram-negative bacterial infection. IL-22, produced by TH17 cells, is crucial for maintaining epithelial barrier function and enhancing antimicrobial activity. These findings support the concept that the TH1