Legionella pneumophila is an opportunistic pathogen of humans and the major cause of an acute pneumonia known as Legionnaire’s Disease. Recently, we observed that monocyte-derived dendritic cells (moDC) are recruited rapidly into the lungs of mice infected with live L. pneumophila. We also found that CCR2-deficient mice, which exhibit decreased moDC recruitment, showed increased bacterial burden in the lung compared to WT mice after L. pneumophila infection. The fact that L. pneumophila does not replicate in moDC suggests these cells might be important for killing bacteria during infection. We also observed that IFNγ produced by memory T cells in the acute phase of L. pneumophila infection was critical for the control of L. pneumophila replication in the lung and that IFNγ was important for moDC maturation (MHC II expression). To understand the possible functions and killing mechanisms of moDC, we sorted moDC from WT and IFNγ-/- mice 3 days after L. pneumophila infection and performed RNA sequencing. Among the most strongly upregulated genes were interferon-stimulated GTPases (ISGs), such as the 65-67 kDa guanylate-binding proteins (GBPs) and 47 kDa immunity-related GTPases (IRGs). These proteins are believed function in cell-autonomous immunity, which allow host cells to kill pathogens or restrict their replication, although their mechanism of action is unknown. In other work, we have found that IL-22 mRNA expression is robustly upregulated in the lungs of mice 2 days after infection and IL-22-deficient mice exhibit higher bacterial loads and severe weight loss (20%-25%) 4 days after infection. Given that the IL-22R is predominantly expressed on the surface of epithelial cells, we will investigate whether IL-22 functions in restraining L. pneumophila replication in epithelial cells in vivo.