Components of murine innate and adaptive immune responses to Francisella. (1) The initial interaction of Francisella with host cells, such as macrophages, dendritic cells, epithelial cells, and endothelial cells, stimulates production of pro-inflammatory cytokines and chemokines (2a) in a manner that is dependent upon MyD88, TLR2, and other unidentified receptors that signal through MyD88. Bacterial DNA engagement of the NOD-like receptor (NLR) AIM2 may also be critical for inflammasome assembly and release of IL-1β. Simultaneously, important innate immune cells recruited to the area of infection produce effector cytokines such as IL-12p40, TNF-α, IFN-γ, and IL-17A (2b) that influence T cell development (3), and induce host cell production of antimicrobial molecules (4). In addition to the classic TH1-type cytokines, other mediators include mast cell production of IL-4, which can directly inhibit Francisella intramacrophage growth, and B-1a B cell production of anti-LPS antibodies that limit intraperitoneal infection. PMNs are essential for survival of Francisella infections initiated via some routes, but fail to eradicate intracellular organisms in vitro, so their contribution to infection remains unclear. After several days, activation and expansion of Francisella-specific T cells and B cells occurs (3). αβ T cells are essential for clearance of primary infection, and produce effector cytokines such as IL-17A and IFN-γ, as well as the membrane-bound and soluble forms of TNF-α. These factors presumably amplify and extend activation of infected host cells to limit Francisella intracellular growth through production of reactive oxygen and nitrogen intermediates, as well as other unidentified antimicrobials (4). Asterisks (*) indicate host cells that have been shown to harbor intracellular Francisella. The blue box indicates cell types that are neither fully innate nor adaptive, based on classical definitions.