A novel role for Irgm1 in immune homeostasis (MUC1P.906)

Abstract Irgm1 is an IFN-inducible GTPase that mediates host resistance to intracellular pathogens. We sought to define the role of Irgm1 in pulmonary immune cell homeostasis by profiling steady state and pathogen-induced immunity in the lungs of Irgm1-/- mice. The lungs of naïve Irgm1-/- mice displayed abnormal bronchiolocentric cellular infiltration composed predominantly of B cells with focal collections of T cells, associated with increased lung and airway cytokines. Compared to WT controls, naïve Irgm1-/- mice had elevated serum and airway levels of immunoglobulins, suggesting dysregulated B cell function. B cells were found to be reduced in the blood of Irgm1-/- mice, and B cell precursors were also decreased in the bone marrow. Whereas B2 and B1a cells were elevated in the Irgm1-/- lung, B1a cells were reduced in the peritoneal cavity, suggesting abnormal trafficking of B cell subsets. Irgm1-/- mice had increased influx of neutrophils, chemokines, cytokines, and IgM into the airspace after exposure to inhaled LPS and/or S. pneumoniae. Pathogen clearance from the lung and survival were increased in Irgm1-/- mice upon challenge with S. pneumoniae. Future studies are planned to better define the mechanism of B cell dys-homeostasis, determine whether Irgm1-/- mice have autoimmunity, and define whether the enhanced host defense response and survival of Irgm1-/- mice against S. pneumoniae derives from increased number and function of innate B cells and their products.