Interleukin-27 orchestrates lymphocyte responses and disease severity during Legionella infection in the lung 2083

Abstract Description Legionnaires’ disease (LD) is a severe respiratory illness caused by Legionella spp., with a 7-10% fatality rate in the US and limited knowledge of its pathobiology. Interleukin (IL)-27 is an immunomodulatory cytokine that signals through the IL-27RA and gp130 receptors. Here, we show that IL-27 modulates lymphocyte-specific responses in the lung during Legionella pneumonia. IL-27 was highly elevated in the bronchoalveolar lavage fluid (BALF) of patients with LD compared to healthy controls (p < 0.001). Comparable results were noted in C57BL/6 mice, with rapid IL-27 induction 24h after L. pneumophila infection. Il-27p28 mRNA was highest in alveolar macrophages, and recruited monocytes in the BALF while IL-27RA was detected in NK and T cells. Global IL-27RA-/- mice showed less severe disease, increased NK and T cell activity, and higher protective IFN-γ levels. These findings were concordant with the highly virulent L. longbeachae. IL-27 chiefly affected immunopathology but not bacterial burden. Single-cell CITE-seq using BALF from L. pneumophila-infected IL27RA-/- mice revealed enhanced expression of the activation markers CD25 and CD69 in NK and T cells, and co-stimulatory over co-inhibitory receptors in T cells versus wild type mice. NK cell-specific IL-27RA deletion worsened disease, while CD8+ T cell-specific deletion had no effect. In conclusion, cell type-specific targeting of IL-27RA activity could be a novel therapeutic approach in treating Legionnaires’ disease. Funding Sources This work was funded by the National Institutes of Health (R01HL166588 to M.B.), the Federal Ministry of Education and Research (01EO1003, 01EO1503 to M.B.), and the Deutsche Forschungsgemeinschaft (BO3482/3-3, BO3482/4-1 to M.B.). Topic Categories Cytokines and Chemokines and Their Receptors (CCR)