Abstract
Legionella pneumophila is the causative agent of Legionnaires’ disease, a potentially fatal lung infection. Alveolar macrophages support intracellular replication of L. pneumophila, however the contributions of other immune cell types to bacterial killing during infection are unclear. Here, we used recently described methods to characterise the major inflammatory cells in lung after acute respiratory infection of mice with L. pneumophila. We observed that the numbers of alveolar macrophages rapidly decreased after infection coincident with a rapid infiltration of the lung by monocyte-derived cells (MC), which, together with neutrophils, became the dominant inflammatory cells associated with the bacteria. Using mice in which the ability of MC to infiltrate tissues is impaired it was found that MC were required for bacterial clearance and were the major source of IL12. IL12 was needed to induce IFNγ production by lymphoid cells including NK cells, memory T cells, NKT cells and γδ T cells. Memory T cells that produced IFNγ appeared to be circulating effector/memory T cells that infiltrated the lung after infection. IFNγ production by memory T cells was stimulated in an antigen-independent fashion and could effectively clear bacteria from the lung indicating that memory T cells are an important contributor to innate bacterial defence. We also determined that a major function of IFNγ was to stimulate bactericidal activity of MC. On the other hand, neutrophils did not require IFNγ to kill bacteria and alveolar macrophages remained poorly bactericidal even in the presence of IFNγ. This work has revealed a cooperative innate immune circuit between lymphoid cells and MC that combats acute L. pneumophila infection and defines a specific role for IFNγ in anti-bacterial immunity.
Highlights
Innate immune responses in infected peripheral tissues are essential for controlling invading pathogens in the early phases of infection to prevent rapid pathogen replication and widespread dissemination
Within 24 h of infection with L. pneumophila, neutrophils and monocyte-derived cells (MC) became the dominant phagocytic cell types in the lung and by day 3 the numbers of MC were comparable to neutrophils (Fig 1B)
In similar experiments we found that bacterial number peaks at day 1–2 and we have previously published that the number of Legionella+ neutrophils, which peaks at day 2, is a reliable indication of bacterial load [24].) cDC increased in number and rivalled alveolar macrophages (AM) in abundance by day 3 (Fig 1B)
Summary
Innate immune responses in infected peripheral tissues are essential for controlling invading pathogens in the early phases of infection to prevent rapid pathogen replication and widespread dissemination. Despite this vital role, the main cells and factors that control innate immune responses in tissues are poorly defined. Components of the innate immune response to pathogens have mostly been studied in isolation and there are few examples where the interplay between distinct innate components that mediate pathogen clearance in vivo is well understood. Since the exact developmental origins and functions of differentiated monocytes in inflammatory sites is usually unclear a recent proposal suggests the term monocyte-derived cell (MC) [5], which we have adopted here
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